2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors

ABSTRACT

The application claims a compound of the formula 
     
       
         
         
             
             
         
       
         
         
           
             or a salt, a hydrate, or a hydrate of a salt thereof. 
           
         
       
    
     The compounds inhibit cGMP-metabolizing phosphodiesterases and are suitable for use as active compounds in pharmaceuticals, for the treatment of erectile dysfunction.

The present invention relates to 2-phenyl-substitutedimidazotriazinones, to processes for their preparation and to their useas pharmaceuticals, in particular as inhibitors of cGMP-metabolizingphosphodiesterases.

The published specification DE 28 11 780 describes imidazotriazines asbronchodilators having spasmolytic activity and inhibitory activityagainst phosphodiesterases which metabolize cyclic adenosinmonophosphate (cAMP-PDEs, nomenclature according to Beavo: PDE-III andPDE-IV). An inhibitory action against phosphodiesterases whichmetabolize cyclic guanosin monophosphate (cGMP-PDEs, nomenclatureaccording to Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11,150-155, 1990) PDE-I, PDE-II and PDE-V) has not been described.Compounds having a sulphonamide group in the aryl radical in the2-position are not claimed. Furthermore, FR 22 13 058, CH 59 46 71, DE22 55 172, DE 23 64 076 and EP 000 9384 describe imidazotriazinoneswhich do not have a substituted aryl radical in the 2-position and arelikewise said to be bronchodilators having cAMP-PDE inhibitory action.

WO 94/28902 describes pyrazolopyrimidinones which are suitable fortreating impotence.

The compounds according to the invention are potent inhibitors either ofone or of more of the phosphodiesterases which metabolize cyclicguanosin 3′,5′-monophosphate (cGMP-PDEs). According to the nomenclatureof Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990)these are the phosphodiesterase isoenzymes PDE-I, PDE-II and PDE-V.

An increase of the cGMP concentration can lead to beneficialantiaggregatory, antithrombotic, antiprolific, antivasospastic,vasodilative, natriuretic and diuretic effects. It can influence theshort- or long-term modulation of vascular and cardiac inotropy, of thepulse and of cardiac conduction (J. C. Stoclet, T. Keravis, N. Komas andC. Kugnier, Exp. Opin. Invest. Drugs (1995), 4 (11), 1081-1100).

The present invention, accordingly, provides 2-phenyl-substitutedimidazotriazinones of the general formula (I)

in which

-   -   R¹ represents hydrogen or straight-chain or branched alkyl        having up to 4 carbon atoms,    -   R² represents straight-chain alkyl having up to 4 carbon atoms,    -   R³ and R⁴ are identical or different and each represents        hydrogen or represents straight-chain or branched alkenyl or        alkoxy having in each case up to 8 carbon atoms, or        -   represents a straight-chain or branched alkyl chain having            up to 10 carbon atoms which is optionally interrupted by an            oxygen atom and which is optionally mono- or polysubstituted            by identical or different substituents selected from the            group consisting of trifluoromethyl, trifluoromethoxy,            hydroxyl, halogen, carboxyl, benzyloxycarbonyl,            straight-chain or branched alkoxycarbonyl having up to 6            carbon atoms and/or by radicals of the formulae —SO₃H,            -(A)_(a)-NR⁷R⁸, —O—CO—NR^(7′)R^(8′), —S(O)_(b)—R⁹,            —P(O)(OR¹⁰)(OR¹¹),

-   -   -   in which        -   a and b are identical or different and each represents a            number 0 or 1,        -   A represents a radical CO or SO₂,        -   R⁷, R^(7′), R⁸ and R^(8′) are identical or different and            each represents hydrogen, or            -   represents cycloalkyl having 3 to 8 carbon atoms, aryl                having 6 to 10 carbon atoms, a 5- to 6-membered                unsaturated, partially unsaturated or saturated,                optionally benzo-fused heterocycle having up to 3                heteroatoms from the group consisting of S, N and O,                where the abovementioned ring systems are optionally                mono- or polysubstituted by identical or different                substituents selected from the group consisting of                hydroxyl, nitro, trifluoromethyl, trifluoromethoxy,                carboxyl, halogen, straight-chain or branched alkoxy or                alkoxycarbonyl having in each case up to 6 carbon atoms                or by a group of the formula —(SO₂)_(c)—NR¹²R¹³,        -   in which        -   c represents a number 0 or 1,        -   R¹² and R¹³ are identical or different and each represents            hydrogen or straight-chain or branched alkyl having up to 5            carbon atoms,

    -   or

    -   R⁷, R^(7′), R⁸ and R^(8′) each represent straight-chain or        branched alkoxy having up to 6 carbon atoms, or        -   represents straight-chain or branched alkyl having up to 8            carbon atoms which is optionally mono- or polysubstituted by            identical or different substituents selected from the group            consisting of hydroxyl, halogen, aryl having 6 to 10 carbon            atoms, straight-chain or branched alkoxy or alkoxycarbonyl            having in each case up to 6 carbon atoms or by a group of            the formula —(CO)_(d)—NR¹⁴R¹⁵,        -   in which        -   R¹⁴ and R¹⁵ are identical or different and each represents            hydrogen or straight-chain or branched alkyl having up to 4            carbon atoms,        -   and        -   d represents a number 0 or 1,

    -   or

    -   R⁷ and R⁸ and/or R^(7′) and R^(8′) together with the nitrogen        atom form a 5- to 7-membered saturated heterocycle which may        optionally contain a further heteroatom from the group        consisting of S and O or a radical of the formula —NR¹⁶,        -   in which        -   R¹⁶ represents hydrogen, aryl having 6 to 10 carbon atoms,            benzyl, a 5- to 7-membered aromatic or saturated heterocycle            having up to 3 heteroatoms from the group consisting of S, N            and O which is optionally substituted by methyl, or            -   represents straight-chain or branched alkyl having up to                6 carbon atoms which is optionally substituted by                hydroxyl,

    -   R⁹ represents aryl having 6 to 10 carbon atoms, or represents        straight-chain or branched alkyl having up to 4 carbon atoms,

    -   R¹⁰ and R¹¹ are identical or different and each represents        hydrogen or straight-chain or branched alkyl having up to 4        carbon atoms,        -   and/or the alkyl chain listed above under R³/R⁴ is            optionally substituted by cycloalkyl having 3 to 8 carbon            atoms, aryl having 6 to 10 carbon atoms or by a 5- to            7-membered partially unsaturated, saturated or unsaturated,            optionally benzo-fused heterocycle which may contain up to 4            heteroatoms from the group consisting of S, N and O or a            radical of the formula —NR¹⁷,        -   in which        -   R¹⁷ represents hydrogen, hydroxyl, formyl, trifluoromethyl,            straight-chain or branched acyl or alkoxy having in each            case up to 4 carbon atoms,            -   or represents straight-chain or branched alkyl having up                to 6 carbon atoms which is optionally mono- or                polysubstituted by identical or different substituents                selected from the group consisting of hydroxyl and                straight-chain or branched alkoxy having up to 6 carbon                atoms,        -   and where aryl and the heterocycle are optionally mono- or            polysubstituted by identical or different substituents            selected from the group consisting of nitro, halogen, —SO₃H,            straight-chain or branched alkyl or alkoxy having in each            case up to 6 carbon atoms, hydroxyl, trifluoromethyl,            trifluoromethoxy and/or by a radical of the formula            —SO₂—NR¹⁸R¹⁹,        -   in which        -   R¹⁸ and R¹⁹ are identical or different and each represents            hydrogen or straight-chain or branched alkyl having up to 6            carbon atoms,

    -   and/or

    -   R³ or R⁴ represents a group of the formula —NR²⁰R²¹,        -   in which        -   R²⁰ and R²¹ have the meanings of R¹⁸ and R¹⁹ given above and            are identical to or different from them,

    -   and/or

    -   R³ or R⁴ represents adamantyl, or represents radicals of the        formulae

-   -   or represents cycloalkyl having 3 to 8 carbon atoms, aryl having        6 to 10 carbon atoms or represents a 5- to 7-membered partially        unsaturated, saturated or unsaturated, optionally benzo-fused        heterocycle which may contain up to 4 heteroatoms from the group        consisting of S, N and O, or a radical of the formula —NR²²,    -   in which    -   R²² has the meaning of R¹⁶ given above and is identical to or        different from it, or        -   represents carboxyl, formyl or straight-chain or branched            acyl having up to 5 carbon atoms,    -   and where cycloalkyl, aryl and/or the heterocycle are optionally        mono- or polysubstituted by identical or different substituents        selected from the group consisting of halogen, triazolyl,        trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or        branched acyl or alkoxycarbonyl having in each case up to 6        carbon atoms, nitro and/or by groups of the formulae —SO₃H,        —OR²³, (SO₂)_(e)NR²⁴R²⁵, —P(O)(OR²⁶)(OR²⁷),    -   in which    -   e represents a number 0 or 1,    -   R²³ represents a radical of the formula

-   -    or        -   represents cycloalkyl having 3 to 7 carbon atoms, or        -   represents hydrogen or straight-chain or branched alkyl            having up to 4 carbon atoms which is optionally substituted            by cycloalkyl having 3 to 7 carbon atoms, benzyloxy,            tetrahydropyranyl, tetrahydrofuranyl, straight-chain or            branched alkoxy or alkoxycarbonyl having in each case up to            6 carbon atoms, carboxyl, benzyloxycarbonyl or phenyl which            for its part may be mono- or polysubstituted by identical or            different substituents selected from the group consisting of            straight-chain or branched alkoxy having up to 4 carbon            atoms, hydroxyl and halogen,        -   and/or alkyl which is optionally substituted by radicals of            the formulae —CO—NR²⁸R²⁹ or —CO—R³⁰,        -   in which        -   R²⁸ and R²⁹ are identical or different and each represents            hydrogen or straight-chain or branched alkyl having up to 8            carbon atoms, or        -   R²⁸ and R²⁹ together with the nitrogen atom form a 5- to            7-membered saturated heterocycle which may optionally            contain a further heteroatom from the group consisting of S            and O,        -   and        -   R³⁰ represents phenyl or adamantyl,    -   R²⁴ and R²⁵ have the meanings of R¹⁸ and R¹⁹ given above and are        identical to or different from them,    -   R²⁶ and R²⁷ have the meanings of R¹⁰ and R¹¹ given above and are        identical to or different from them    -   and/or cycloalkyl, aryl and/or the heterocycle are optionally        substituted by straight-chain or branched alkyl having up to 6        carbon atoms which is optionally substituted by hydroxyl,        carboxyl, by a 5- to 7-membered heterocycle having up to 3        heteroatoms from the group consisting of S, N and O, or by        groups of the formula —SO₂—R³¹, P(O)(OR³²)(OR³³) or —NR³⁴R³⁵,    -   in which    -   R³¹ represents hydrogen or has the meaning of R⁹ given above and        is identical to or different from it,    -   R³² and R³³ have the meanings of R¹⁰ and R¹¹ given above and are        identical to or different from them,    -   R³⁴ and R³⁵ are identical or different and each represents        hydrogen or straight-chain or branched alkyl having up to 6        carbon atoms which is optionally substituted by hydroxyl or by        straight-chain or branched alkoxy having up to 4 carbon atoms,        or    -   R³⁴ and R³⁵ together with the nitrogen atom form a 5- to        6-membered saturated heterocycle which may contain a further        heteroatom from the group consisting of S and O, or a radical of        the formula —NR³⁶,        -   in which        -   R³⁶ represents hydrogen, hydroxyl, straight-chain or            branched alkoxycarbonyl having up to 7 carbon atoms or            straight-chain or branched alkyl having up to 5 carbon atoms            which is optionally substituted by hydroxyl,    -   or    -   R³ and R⁴ together with the nitrogen atom form a 5- to        7-membered unsaturated or saturated or partially unsaturated,        optionally benzo-fused heterocycle which may optionally contain        up to 3 heteroatoms from the group consisting of S, N and O, or        a radical of the formula —NR⁷,        -   in which        -   R³⁷ represents hydrogen, hydroxyl, formyl, trifluoromethyl,            straight-chain or branched acyl, alkoxy or alkoxycarbonyl            having in each case up to 4 carbon atoms,            -   or represents straight-chain or branched alkyl having up                to 6 carbon atoms which is optionally mono- or                polysubstituted by identical or different substituents                selected from the group consisting of hydroxyl,                trifluoromethyl, carboxyl, straight-chain or branched                alkoxy or alkoxycarbonyl having in each case up to 6                carbon atoms, or by groups of the formula                -(D)_(f-)NR³⁸R³⁹, —CO—(CH₂)_(g)—O—CO—R⁴⁰,                —CO—(CH₂)_(h)—OR⁴¹ or —P(O)(OR⁴²)(OR⁴³),            -   in which        -   g and h are identical or different and each represents a            number 1, 2, 3 or 4,        -   and        -   f represents a number 0 or 1,        -   D represents a group of the formula —CO or —SO₂,        -   R³⁸ and R³⁹ are identical or different and each has the            meaning of R⁷ and R⁸ given above,        -   R⁴⁰ represents straight-chain or branched alkyl having up to            6 carbon atoms,        -   R⁴¹ represents straight-chain or branched alkyl having up to            6 carbon atoms,        -   R⁴² and R⁴³ are identical or different and each represents            hydrogen or straight-chain or branched alkyl having up to 4            carbon atoms,    -   or    -   R³⁷ represents a radical of the formula —(CO)_(i)-E,        -   in which        -   i represents a number 0 or 1,        -   E represents cycloalkyl having 3 to 7 carbon atoms or            benzyl, represents aryl having 6 to 10 carbon atoms or a 5-            to 6-membered aromatic heterocycle having up to 4            heteroatoms from the group consisting of S, N and O, where            the abovementioned ring systems are optionally mono- or            polysubstituted by identical or different constituents            selected from the group consisting of nitro, halogen, —SO₃H,            straight-chain or branched alkoxy having up to 6 carbon            atoms, hydroxyl, trifluoromethyl, trifluoromethoxy, or by a            radical of the formula —SO₂—NR⁴⁴R⁴⁵,            -   in which            -   R⁴⁴ and R⁴⁵ have the meanings of R¹⁸ and R¹⁹ given above                and are identical to or different from them,    -   or    -   E represents radicals of the formulae

-   -   and the heterocycle listed under R³ and R⁴, which is formed        together with the nitrogen atom, is optionally mono- or        polysubstituted, if appropriate also geminally, by identical or        different substituents selected from the group consisting of        hydroxyl, formyl, carboxyl, straight-chain or branched acyl or        alkoxycarbonyl having in each case up to 6 carbon atoms, nitro        and groups of the formulae —P(O)(OR⁴⁶)(OR⁴⁷),

-   -   in which    -   R⁴⁶ and R⁴⁷ have the meanings of R¹⁰ and R¹¹ given above and are        identical to or different from them,    -   R⁴⁸ represents hydroxyl or straight-chain or branched alkoxy        having up to 4 carbon atoms,    -   j represents a number 0 or 1, and    -   R⁴⁹ and R⁵⁰ are identical or different and have the meanings of        R¹⁴ and R¹⁵ given above,        -   and/or the heterocycle listed under R³ and R⁴, which is            formed together with the nitrogen atom, is optionally            substituted by straight-chain or branched alkyl having up to            6 carbon atoms which is optionally mono- or polysubstituted            by identical or different substituents selected from the            group consisting of hydroxyl, halogen, carboxyl, cycloalkyl            or cycloalkyloxy having in each case 3 to 8 carbon atoms,            straight-chain or branched alkoxy or alkoxycarbonyl having            in each case up to 6 carbon atoms, or by a radical of the            formula —SO₃H, —NR⁵¹R⁵² or P(O)OR⁵³OR⁵⁴,        -   in which        -   R⁵¹ and R⁵² are identical or different and each represents            hydrogen, phenyl, carboxyl, benzyl or straight-chain or            branched alkyl or alkoxy having in each case up to 6 carbon            atoms,        -   R⁵³ and R⁵⁴ are identical or different and have the meanings            of R¹⁰ and R¹¹ given above,        -   and/or the alkyl is optionally substituted by aryl having 6            to 10 carbon atoms which for its part may be mono- or            polysubstituted by identical or different substituents            selected from the group consisting of halogen, hydroxyl,            straight-chain or branched alkoxy having up to 6 carbon            atoms, or by a group of the formula —NR^(51′)R^(52′),        -   in which        -   R^(51′) and R^(52′) have the meanings of R⁵¹ and R⁵² given            above and are identical to or different from them,        -   and/or the heterocycle listed under R³ and R⁴, which is            formed together with the nitrogen atom, is optionally            substituted by aryl having 6 to 10 carbon atoms or by a 5-            to 7-membered saturated, partially unsaturated or            unsaturated heterocycle having up to 3 heteroatoms from the            group consisting of S, N and O, optionally also attached via            a nitrogen function, where the ring systems for their part            may be substituted by hydroxyl or by straight-chain or            branched alkyl or alkoxy having in each case up to 6 carbon            atoms,    -   or    -   R³ and R⁴ together with the nitrogen atom form radicals of the        formulae

-   -   R⁵ and R⁶ are identical or different and each represents        hydrogen, straight-chain or branched alkyl having up to 6 carbon        atoms, hydroxyl or represents straight-chain or branched alkoxy        having up to 6 carbon atoms,    -   and their salts, hydrates, N-oxides and isomeric forms.

The compounds according to the invention may exist in stereoisomericforms which are related either as image and mirror image (enantiomers),or which are not related as image and mirror image (diastereomers). Theinvention relates both to the enantiomers or diastereomers and to theirrespective mixtures. The racemic forms can, just like the diastereomers,be separated in a known manner into the stereoisomerically pureconstituents.

The substances according to the invention may also be present as salts.In the context of the invention, preference is given to physiologicallyacceptable salts.

Physiologically acceptable salts can be salts of the compounds accordingto the invention with inorganic or organic acids. Preference is given tosalts with inorganic acids, such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid or sulphuric acid, or to salts withorganic carboxylic or sulphonic acids, such as, for example, aceticacid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid,lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonicacid, phenylsulphonic acid, toluenesulphonic acid ornaphthalenedisulphonic acid.

Physiologically acceptable salts can also be metal or ammonium salts ofthe compounds according to the invention. Particular preference is givento, for example, sodium, potassium, magnesium or calcium salts, and alsoto ammonium salts which are derived from ammonia or organic amines, suchas, for example, ethylamine, di- or triethylamine, di- ortriethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine,lysine, ethylenediamine or 2-phenylethylamine.

In the context of the invention, an optionally benzo-fused heterocyclegenerally represents a saturated, partially unsaturated or unsaturated5- to 7-membered heterocycle which may contain up to 4 heteroatoms fromthe group consisting of S, N and O. Examples which may be mentioned are:azepine, diazepine, indolyl, isoquinolyl, quinolyl, benzo[b]thiophene,benzo[b]furanyl, pyridyl, thienyl, tetrahydrofuranyl, tetrahydropyranyl,furyl, pyrrolyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl,imidazolyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperazinyl,N-methylpiperazinyl or piperidinyl. Preference is given to quinolyl,furyl, pyridyl, thienyl, piperidinyl, pyrrolidinyl, piperazinyl,azepine, diazepine, thiazolyl, triazolyl, tetrazolyl, tetrahydrofuranyl,tetrahydropyranyl, morpholinyl and thiomorpholinyl.

In the context of the invention, a straight-chain or branched acylradical having 1 to 6 carbon atoms represents, for example acetyl,ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl,isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl. Preference is givento a straight-chain or branched acyl radical having 1 to 4 carbon atoms.Particular preference is given to acetyl and ethylcarbonyl.

In the context of the invention, a straight-chain or branched alkoxyradical having 1 to 6 or 1 to 4 carbon atoms represents methoxy, ethoxy,n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. Preferenceis given to a straight-chain or branched alkoxy radical having 1 to 6, 1to 4 or 1 to 3 carbon atoms. Particular preference is given to astraight-chain or branched alkoxy radical having 1 to 3 carbon atoms.

In the context of the invention, a straight-chain or branchedalkoxycarbonyl radical having 1 to 6 carbon atoms represents, forexample, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl and tert-butoxycarbonyl. Preference is given to astraight-chain or branched alkoxycarbonyl radical having 1 to 4 carbonatoms. Particular preference is given to a straight-chain or branchedalkoxycarbonyl radical having 1 to 3 carbon atoms.

In the context of the invention, a straight-chain or branched alkylradical having 1 to 4, 1 to 6, 1 to 8 and 1-10 carbon atoms represents,for example, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Preference is given tostraight-chain or branched alkyl radicals having 1 to 3, 1 to 4 or 1 to8 carbon atoms. Particular preference is given to straight-chain orbranched alkyl radicals having 1 to 4 or 1 to 3 carbon atoms.

In the context of the invention, straight-chain alkyl having up to 4carbon atoms represents, for example, methyl, ethyl, n-propyl andn-butyl.

(C₆-C₁₀)-Aryl generally represents an aromatic radical having 6 to 10carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

In the context of the invention, cycloalkyl having 3 to 8 or 3 to 7carbon atoms represents, for example, cyclopropyl, cyclopentyl,cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. Preference is givento: cyclopropyl, cyclopentyl and cyclohexyl.

In the context of the invention, cycloalkyloxy having 3 to 8 carbonatoms represents cyclopropyloxy, cyclopentyloxy, cyclobutyloxy,cyclohexyloxy, cycloheptyloxy or cyclooctyloxy. Preference is given to:cyclopropyloxy, cyclopentyloxy and cyclohexyloxy.

In the context of the invention, halogen generally represents fluorine,chlorine, bromine and iodine. Preference is given to fluorine, chlorineand bromine. Particular preference is given to fluorine and chlorine.

In the context of the invention and depending on the abovementionedsubstituents, a 5- to 6-membered or 7-membered saturated heterocycle,which may contain a further heteroatom from the group consisting of S, Nand O represents, for example, morpholinyl, piperidinyl, piperazinyl,tetrahydropyranyl or tetrahydrofuranyl. Preference is given tomorpholinyl, tetrahydropyranyl, piperidinyl and piperazinyl.

In the context of the invention, a 5- to 6-membered aromatic heterocyclehaving up to 3 or 4 heteroatoms from the group consisting of S, O and Nrepresents, for example, pyridyl, pyrimidyl, pyridazinyl, thienyl,furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Preference is givento pyridyl, pyrimidyl, pyridazinyl, furyl and thiazolyl.

In the context of the invention, a 5- to 6-membered unsaturated,partially unsaturated and saturated heterocycle which may contain up to3 or 4 heteroatoms from the group consisting of S, O and N represents,for example, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl,thiazolyl, oxazolyl, imidazolyl, piperidinyl, piperazinyl ormorpholinyl. Preference is given to pyridyl, pyrimidyl, piperazinyl,pyridazinyl, morpholinyl, furyl and thiazolyl.

The compounds according to the invention, in particular the salts, mayalso be present as hydrates. In the context of the invention, hydratesare those compounds which contain water in the crystal. Such compoundsmay contain one or more, typically 1 to 5, equivalents of water.Hydrates can be prepared, for example, by crystallizing the compound inquestion from water or from a water-containing solvent.

Preference is given to compounds of the general formula (I) according tothe invention

in which

-   R¹ represents straight-chain or branched alkyl having up to 3 carbon    atoms,-   R² represents straight-chain alkyl having up to 3 carbon atoms,-   R³ and R⁴ are identical or different and each represents hydrogen or    represents straight-chain or branched alkenyl or alkoxy having in    each case up to 6 carbon atoms, or    -   represents a straight-chain or branched alkyl chain having up to        8 carbon atoms which is optionally interrupted by an oxygen atom        and which is optionally mono- to trisubstituted by identical or        different substituents selected from the group consisting of        hydroxyl, fluorine, chlorine, carboxyl, benzyloxycarbonyl,        straight-chain or branched alkoxycarbonyl having up to 5 carbon        atoms, and/or by radicals of the formulae —SO₃H, -(A)_(a)-NR⁷R⁸,        —O—CO—NR^(7′)R^(8′), —S(O)_(b)—R⁹, —P(O)(OR¹⁰)(OR¹¹),

-   -   in which    -   a and b are identical or different and each represents a number        0 or 1,    -   A represents a radical CO or SO₂,    -   R⁷, R^(7′), R⁸ and R^(8′) are identical or different and each        represents hydrogen, or cyclopropyl, cyclopentyl, cyclohexyl,        cycloheptyl, phenyl, piperidinyl and pyridyl, where the        abovementioned ring systems are optionally mono- to        trisubstituted by identical or different substituents selected        from the group consisting of hydroxyl, nitro, trifluoromethyl,        trifluoromethoxy, carboxyl, fluorine, chlorine, straight-chain        or branched alkoxy or alkoxycarbonyl having in each case up to 4        carbon atoms, or by a group of the formula —(SO₂)_(c)—NR¹²R¹³,        -   in which        -   c represents a number 0 or 1,        -   R¹² and R¹³ are identical or different and each represents            hydrogen or straight-chain or branched alkyl having up to 4            carbon atoms,    -   or    -   R⁷, R^(7′), R⁸ and R^(8′) each represent straight-chain or        branched alkoxy having up to 3 carbon atoms, or        -   represents straight-chain or branched alkyl having up to 7            carbon atoms which is optionally mono- or polysubstituted by            identical or different substituents selected from the group            consisting of hydroxyl, fluorine, chlorine, phenyl,            straight-chain or branched alkoxy or alkoxycarbonyl having            in each case up to 4 carbon atoms, or by a group of the            formula —(CO)_(d)—NR¹⁴R¹⁵,        -   in which        -   R¹⁴ and R¹⁵ are identical or different and each represents            hydrogen or straight-chain or branched alkyl having up to 3            carbon atoms,        -   and        -   d represents a number 0 or 1,    -   or    -   R⁷ and R⁸ and/or R^(7′) and R^(8′) together with the nitrogen        atom form a pyrrolidinyl, morpholinyl, piperidinyl or triazolyl        ring or radicals of the formulae

-   -   -   in which        -   R¹⁶ represents hydrogen, phenyl, benzyl, morpholinyl,            pyrrolidinyl, piperidinyl, piperazinyl or            N-methylpiperazinyl, or represents straight-chain or            branched alkyl having up to 5 carbon atoms which is            optionally substituted by hydroxyl,

    -   R⁹ represents straight-chain or branched alkyl having up to 3        carbon atoms,

    -   R¹⁰ and R¹¹ are identical or different and each represents        hydrogen or straight-chain or branched alkyl having up to 3        carbon atoms,        -   and/or the alkyl chain listed under R³/R⁴ is optionally            substituted by cyclopropyl, cyclopentyl, cyclohexyl,            cycloheptyl, phenyl, pyridyl, quinolyl, pyrrolidinyl,            pyrimidyl, morpholinyl, furyl, piperidinyl,            tetrahydrofuranyl or by radicals of the formulae

-   -   -   in which        -   R¹⁷ represents hydrogen, hydroxyl, formyl, trifluoromethyl,            straight-chain or branched acyl or alkoxy having in each            case up to 3 carbon atoms,            -   or represents straight-chain or branched alkyl having up                to 4 carbon atoms which is optionally mono- to                trisubstituted by identical or different substituents                selected from the group consisting of hydroxyl and                straight-chain or branched alkoxy having up to 4 carbon                atoms,        -   and where phenyl and the heterocycles are optionally mono-            to trisubstituted by identical or different substituents            selected from the group consisting of nitro, fluorine,            chlorine, —SO₃H, straight-chain or branched alkyl or alkoxy            having in each case up to 4 carbon atoms, hydroxyl, and/or            by a radical of the formula —SO₂—NR¹⁸R¹⁹,        -   in which        -   R¹⁸ and R¹⁹ are identical or different and each represents            hydrogen or straight-chain or branched alkyl having up to 4            carbon atoms,

    -   and/or

    -   R³ or R represents a group of the formula —NR²⁰R²¹,        -   in which        -   R²⁰ and R²¹ have the meanings of R¹⁸ and R¹⁹ given above and            are identical to or different from them,

    -   and/or

    -   R³ or R⁴ represents adamantyl, or represents radicals of the        formulae

-   -   or represents cyclopentyl, cyclohexyl, cycloheptyl, phenyl,        morpholinyl, oxazolyl, thiazolyl, quinolyl, isoxazolyl, pyridyl,        tetrahydrofuranyl, tetrahydropyranyl or represents radicals of        the formulae

-   -   in which    -   R²² has the meaning of R¹⁶ given above and is identical to or        different from it, or        -   represents carboxyl, formyl or straight-chain or branched            acyl having up to 3 carbon atoms,    -   and where cycloalkyl, phenyl and/or the heterocycles are        optionally mono- to trisubstituted by identical or different        substituents selected from the group consisting of fluorine,        chlorine, triazolyl, trifluoromethyl, trifluoromethoxy,        carboxyl, straight-chain or branched acyl or alkoxycarbonyl        having in each case up to 5 carbon atoms, nitro and/or by groups        of the formulae —SO₃H, OR²³, (SO₂)_(n)NR²⁴R²⁵,        —P(O)(OR²⁶)(OR²⁷),    -   in which    -   e represents a number 0 or 1,    -   R²³ represents a radical of the formula

-   -    or        -   represents cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl            or cycloheptyl,        -   represents hydrogen or straight-chain or branched alkyl            having up to 4 carbon atoms which may optionally be            substituted by cyclopropyl, cyclopentyl, cyclohexyl,            benzyloxy, tetrahydropyranyl, tetrahydrofuranyl,            straight-chain or branched alkoxy or alkoxycarbonyl having            in each case up to 4 carbon atoms, benzyloxycarbonyl or            phenyl which for its part may be mono- or polysubstituted by            identical or different substituents selected from the group            consisting of straight-chain or branched alkoxy having up to            3 carbon atoms, hydroxyl, fluorine and chlorine,        -   and/or where alkyl is optionally substituted by radicals of            the formulae —CO—NR²⁸R²⁹ or —CO—R³⁰,        -   in which        -   R²⁸ and R²⁹ are identical or different and each represents            hydrogen or straight-chain or branched alkyl having up to 5            carbon atoms, or        -   R²⁸ and R²⁹ together with the nitrogen atom form a            morpholinyl, pyrrolidinyl or piperidinyl ring,        -   and        -   R³⁰ represents phenyl or adamantyl,    -   R²⁴ and R²⁵ have the meanings of R¹⁸ and R¹⁹ given above and are        identical to or different from them,    -   R²⁶ and R²⁷ have the meanings of R¹⁰ and R¹¹ given above and are        identical to or different from them        -   and/or cycloalkyl, phenyl and/or the heterocycles are            optionally substituted by straight-chain or branched alkyl            having up to 4 carbon atoms which is optionally substituted            by hydroxyl, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl,            piperidinyl, tetrahydrofuranyl, triazolyl or by groups of            the formula —SO₂—R³¹, —P(O)(OR³²)(OR³³) or —NR³⁴R³⁵,        -   in which        -   R³¹ has the meaning of R⁹ given above and is identical to or            different from it,        -   R³² and R³³ have the meanings of R¹⁰ and R¹¹ given above and            are identical to or different from them,        -   R³⁴ and R³⁵ are identical or different and each represents            hydrogen or straight-chain or branched alkyl having up to 5            carbon atoms which is optionally substituted by hydroxyl or            straight-chain or branched alkoxy having up to 3 carbon            atoms, or        -   R³⁴ and R³⁵ together with the nitrogen atom form a            morpholinyl, triazolyl or thiomorpholinyl ring or a radical            of the formula

-   -   -   -   in which            -   R³⁶ represents hydrogen, hydroxyl, straight-chain or                branched alkoxycarbonyl having up to 5 carbon atoms or                straight-chain or branched alkyl having up to 4 carbon                atoms which is optionally substituted by hydroxyl,

    -   or

    -   R³ and R⁴ together with the nitrogen atom form a morpholinyl,        thiomorpholinyl, pyrrolidinyl, piperidinyl ring, or a radical of        the formula

-   -   -   in which        -   R³⁷ represents hydrogen, hydroxyl, formyl, trifluoromethyl,            straight-chain or branched acyl, alkoxy or alkoxycarbonyl            having in each case up to 4 carbon atoms,            -   or represents straight-chain or branched alkyl having up                to 5 carbon atoms which is optionally mono- to                trisubstituted by identical or different substituents                selected from the group consisting of hydroxyl,                trifluoromethyl, carboxyl, straight-chain or branched                alkoxy or alkoxycarbonyl having in each case up to 4                carbon atoms, or by groups of the formula                -(D)_(f-)NR³⁸R³⁹, —CO—(CH₂)_(g)—O—CO—R⁴⁰,                —CO—(CH₂)_(h)—OR⁴¹ or —P(O)(OR⁴²)(OR⁴³),            -   in which            -   g and h are identical or different and each represents a                number 1, 2 or 3,            -   and            -   f represents a number 0 or 1,            -   D represents a group of the formula —CO or —SO₂,            -   R³⁸ and R³⁹ are identical or different and have the                meanings of R⁷ and R⁸ given above,            -   R⁴⁰ represents straight-chain or branched alkyl having                up to 4 carbon atoms,            -   R⁴¹ represents straight-chain or branched alkyl having                up to 4 carbon atoms,            -   R⁴² and R⁴³ are identical or different and each                represents hydrogen or straight-chain or branched alkyl                having up to 3 carbon atoms, or

    -   R³⁷ represents a radical of the formula —(CO)_(i)-E,        -   in which        -   represents a number 0 or 1,        -   E represents cyclopentyl, cyclohexyl, cycloheptyl, benzyl,            phenyl, pyridyl, pyrimidyl or furyl, where the            abovementioned ring systems are optionally mono- or            disubstituted by identical or different substituents            selected from the group consisting of nitro, fluorine,            chlorine, —SO₃H, straight-chain or branched alkoxy having up            to 4 carbon atoms, hydroxyl, trifluoromethyl,            trifluoromethoxy or by a radical of the formula            —SO₂—NR⁴⁴R⁴⁵,            -   in which            -   R⁴⁴ and R⁴⁵ have the meanings of R¹⁸ and R¹⁹ given above                and are identical to or different from them,            -   or            -   E represents radicals of the formulae

-   -   -   and the heterocycles listed under R³ and R⁴, which are            formed together with the nitrogen atom, are optionally mono-            to trisubstituted, optionally also geminally, by identical            or different substituents selected from the group consisting            of hydroxyl, formyl, carboxyl, straight-chain or branched            acyl or alkoxycarbonyl having in each case up to 5 carbon            atoms, nitro and groups of the formulae —P(O)(OR⁴⁶)(OR⁴⁷),

-   -   -   in which        -   R⁴⁶ and R⁴⁷ have the meanings of R¹⁰ and R¹¹ given above and            are identical to or different from them,        -   R⁴⁸ represents hydroxyl or straight-chain or branched alkoxy            having up to 3 carbon atoms,        -   j represents a number 0 or 1,        -   and        -   R⁴⁹ and R⁵⁰ are identical or different and have the meanings            of R¹⁴ and R¹⁵ given above,        -   and/or the heterocycles listed under R³ and R⁴, which are            formed together with the nitrogen atom, are optionally            substituted by straight-chain or branched alkyl having up to            5 carbon atoms which is optionally mono- or polysubstituted            by identical or different substituents selected from the            group consisting of hydroxyl, fluorine, chlorine, carboxyl,            cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,            straight-chain or branched alkoxy or alkoxycarbonyl having            in each case up to 4 carbon atoms, or by a radical of the            formula —SO₃H, —NR⁵¹R⁵² or —P(O)OR⁵³OR⁵⁴,        -   in which        -   R⁵¹ and R⁵² are identical or different and each represents            hydrogen, phenyl, carboxyl, benzyl or straight-chain or            branched alkyl or alkoxy having in each case up to 4 carbon            atoms,        -   R⁵³ and R⁵⁴ are identical or different and have the meanings            of R¹⁰ and R¹¹ given above,        -   and/or the alkyl is optionally substituted by phenyl which            for its part may be mono- to trisubstituted by identical or            different substituents selected from the group consisting of            fluorine, chlorine, hydroxyl, straight-chain or branched            alkoxy having up to 4 carbon atoms, or by a group of the            formula —NR^(51′)R^(52′),        -   in which        -   R^(51′) and R^(52′) have the meanings of R⁵¹ and R⁵² given            above and are identical to or different from them,        -   and/or the heterocycles listed under R³ and R⁴, which are            formed together with the nitrogen atom, are optionally            substituted by phenyl, pyridyl, piperidinyl, pyrrolidinyl or            tetrazolyl, optionally also attached via a nitrogen            function, where the ring systems for their part may be            substituted by hydroxyl or by straight-chain or branched            alkyl or alkoxy having in each case up to 5 carbon atoms,

    -   or

    -   R³ and R⁴ together with the nitrogen atom form radicals of the        formulae

-   -   R⁵ and R⁶ are identical or different and each represents        hydrogen, hydroxyl or represents straight-chain or branched        alkoxy having up to 4 carbon atoms,    -   and their salts, N-oxides, hydrates and isomeric forms.

Particular preference is given to compounds of the general formula (I)according to the invention

in which

-   R¹ represents straight-chain or branched alkyl having up to 3 carbon    atoms,-   R² represents straight-chain alkyl having up to 3 carbon atoms,-   R³ and R⁴ are identical or different and each represents hydrogen or    represents straight-chain or branched alkenyl or alkoxy having in    each case up to 4 carbon atoms, or    -   represents a straight-chain or branched alkyl chain having up to        6 carbon atoms which is optionally interrupted by an oxygen atom        and which is optionally mono- to trisubstituted by identical or        different substituents selected from the group consisting of        hydroxyl, fluorine, chlorine, carboxyl, straight-chain or        branched alkoxycarbonyl having up to 4 carbon atoms, and/or by        radicals of the formulae —SO₃H, -(A)_(a)-NR⁷R⁸,        —O—CO—NR^(7′)R^(8′), —S(O)_(b)—R⁹, —P(O)(OR¹⁰)(OR¹¹),

-   -   -   in which        -   a and b are identical or different and each represents a            number 0 or 1,        -   A represents a radical CO or SO₂,        -   R⁷, R^(7′), R⁸ and R^(8′) are identical or different and            each represents hydrogen, or            -   represents cyclopentyl, cyclohexyl, cycloheptyl, phenyl,                piperidinyl and pyridyl, where the abovementioned ring                systems are optionally mono- or disubstituted by                identical or different substituents selected from the                group consisting of hydroxyl, nitro, carboxyl, fluorine,                chlorine, straight-chain or branched alkoxy or                alkoxycarbonyl having in each case up to 3 carbon atoms,                or by a group of the formula —(SO₂)_(c)—NR¹²R¹³,            -   in which        -   c represents a number 0 or 1,        -   R¹² and R¹³ are identical or different and each represents            hydrogen or straight-chain or branched alkyl having up to 3            carbon atoms,

    -   or

    -   R⁷, R^(7′), R⁸ and R^(8′) each represent methoxy, or        -   represent straight-chain or branched alkyl having up to 6            carbon atoms which is optionally mono- or disubstituted by            identical or different substituents selected from the group            consisting of hydroxyl, fluorine, chlorine, phenyl,            straight-chain or branched alkoxy or alkoxycarbonyl having            in each case up to 3 carbon atoms, or by a group of the            formula —(CO)_(d)—NR¹⁴R¹⁵,        -   in which        -   R¹⁴ and R¹⁵ are identical or different and each represents            hydrogen, methyl or ethyl,        -   and        -   d represents a number 0 or 1,

    -   or

    -   R⁷ and R⁸ and/or R^(7′) and R^(8′) together with the nitrogen        atom form a morpholinyl, piperidinyl or triazolyl ring or        radicals of the formulae

-   -   -   in which        -   R¹⁶ represents hydrogen, phenyl, benzyl, morpholinyl,            pyrrolidinyl, piperidinyl, piperazinyl or            N-methylpiperazinyl, or represents straight-chain or            branched alkyl having up to 3 carbon atoms which is            optionally substituted by hydroxyl,

    -   R⁹ represents methyl,

    -   R¹⁰ and R¹¹ are identical or different and each represents        hydrogen, methyl or ethyl,        -   and/or the alkyl chain listed under R³/R⁴ is optionally            substituted by cyclopropyl, cyclopentyl, cyclohexyl,            cycloheptyl, morpholinyl, furyl, tetrahydrofuranyl, or by            radicals of the formulae

-   -   -   in which        -   R¹⁷ represents hydrogen, hydroxyl, formyl, acetyl or alkoxy            having up to 3 carbon atoms,            -   or represents straight-chain or branched alkyl having up                to 3 carbon atoms which is optionally mono- or                disubstituted by identical or different substituents                selected from the group consisting of hydroxyl and                straight-chain or branched alkoxy having up to 3 carbon                atoms,        -   and where phenyl and the heterocycles are optionally mono-            to trisubstituted by identical or different substituents            selected from the group consisting of fluorine, chlorine,            —SO₃H, straight-chain or branched alkyl or alkoxy having in            each case up to 3 carbon atoms, hydroxyl, and/or by a            radical of the formula —SO₂₋NR¹⁸R¹⁹,        -   in which        -   R¹⁸ and R¹⁹ are identical or different and each represents            hydrogen or straight-chain or branched alkyl having up to 3            carbon atoms,

    -   and/or

    -   R³ or R⁴ represents a group of the formula —NR²OR²¹,        -   in which        -   R²⁰ and R²¹ have the meanings of R¹⁸ and R¹⁹ given above and            are identical to or different from them,

    -   and/or

    -   R³ or R⁴ represents adamantyl, or represents radicals of the        formulae

-   -   -   or represents cyclopentyl, cyclohexyl, cycloheptyl, phenyl,            morpholinyl, oxazolyl, thiazolyl, quinolyl, isoxazolyl,            pyridyl, tetrahydrofuranyl, tetrahydropyranyl, or represents            radicals of the formulae

-   -   -   in which        -   R²² has the meaning of R¹⁶ given above and is identical to            or different from it, or represents formyl or acetyl,        -   and where cycloalkyl, phenyl and/or the heterocycles are            optionally mono- or disubstituted by identical or different            substituents selected from the group consisting of fluorine,            chlorine, triazolyl, carboxyl, straight-chain or branched            acyl or alkoxycarbonyl having in each case up to 4 carbon            atoms, nitro, and/or by groups of the formulae —SO₃H, —OR²³,            (SO₂)_(n)NR²⁴R²⁵, —P(O)(OR²⁶)(OR²⁷),        -   in which        -   e represents a number 0 or 1,        -   R²³ represents a radical of the formula

-   -   -    or        -   represents cyclopropyl, cyclopentyl, cyclobutyl or            cyclohexyl, represents hydrogen or straight-chain or            branched alkyl having up to 3 carbon atoms which is            optionally substituted by cyclopropyl, cyclohexyl,            benzyloxy, tetrahydropyranyl, straight-chain or branched            alkoxy or alkoxycarbonyl having in each case up to 3 carbon            atoms, benzyloxycarbonyl or phenyl which for its part may be            mono- or disubstituted by identical or different            substituents selected from the group consisting of methoxy,            hydroxyl, fluorine or chlorine,        -   and/or where alkyl is optionally substituted by radicals of            the formulae —CO—NR²⁸R²⁹ or —CO—R³⁰,        -   in which        -   R²⁸ and R²⁹ are identical or different and each represents            hydrogen or straight-chain or branched alkyl having up to 4            carbon atoms, or        -   R²⁸ and R²⁹ together with the nitrogen atom form a            morpholinyl, pyrrolidinyl or piperidinyl ring,        -   and        -   R³⁰ represents phenyl or adamantyl,

    -   R²⁴ and R²⁵ have the meanings of R¹⁸ and R¹⁹ given above and are        identical to or different from them,

    -   R²⁶ and R²⁷ have the meanings of R¹⁰ and R¹¹ given above and are        identical to or different from them        -   and/or cycloalkyl, phenyl and/or the heterocycles are            optionally substituted by straight-chain or branched alkyl            having up to 3 carbon atoms which is optionally substituted            by hydroxyl, carboxyl, pyridyl, pyrimidyl, pyrrolidinyl,            piperidinyl, tetrahydrofuranyl, triazolyl or by groups of            the formula —SO₂—R³¹, P(O)(OR³²)(OR³³) or —NR³⁴R³⁵,        -   in which        -   R³¹ represents methyl,        -   R³² and R³³ have the meanings of R¹⁰ and R¹¹ given above and            are identical to or different from them,        -   R³⁴ and R³⁵ are identical or different and each represents            hydrogen or straight-chain or branched alkyl having up to 3            carbon atoms which is optionally substituted by hydroxyl or            methoxy, or        -   R³⁴ and R³⁵ together with the nitrogen atom form a            morpholinyl, triazolyl or thiomorpholinyl ring, or a radical            of the formula

-   -   -   -   in which            -   R³⁶ represents hydrogen, hydroxyl, straight-chain or                branched alkoxycarbonyl having up to 3 carbon atoms or                straight-chain or branched alkyl having up to 3 carbon                atoms which is optionally substituted by hydroxyl,

    -   or

    -   R³ and R⁴ together with the nitrogen atom form a morpholinyl,        thiomorpholinyl, pyrrolidinyl, piperidinyl ring, or a radical of        the formula

-   -   -   in which        -   R³⁷ represents hydrogen, hydroxyl, formyl, straight-chain or            branched acyl, alkoxy or alkoxycarbonyl having in each case            up to 3 carbon atoms,            -   or represents straight-chain or branched alkyl having up                to 4 carbon atoms which is optionally mono- or                disubstituted by identical or different substituents                selected from the group consisting of hydroxyl,                straight-chain or branched alkoxy or alkoxycarbonyl                having in each case up to 3 carbon atoms, or by groups                of the formula -(D)_(f-)NR³⁸R³⁹, —CO—(CH₂)_(g)—O—CO—R⁴⁰,                —CO—(CH₂)_(h)—OR⁴¹ or —P(O)(OR⁴²)(OR⁴³),            -   in which            -   g and h are identical or different and each represents a                number 1 or 2,            -   and            -   f represents a number 0 or 1,            -   D represents a group of the formula —CO or —SO₂,            -   R³⁸ and R³⁹ are identical or different and have the                meanings of R⁷ and R⁸ given above,            -   R⁴⁰ represents straight-chain or branched alkyl having                up to 3 carbon atoms,            -   R⁴¹ represents straight-chain or branched alkyl having                up to 3 carbon atoms,            -   R⁴² and R⁴³ are identical or different and each                represents hydrogen, methyl or ethyl,

    -   or

    -   R³⁷ represents a radical of the formula —(CO)_(i)-E,        -   in which        -   i represents a number 0 or 1,        -   E represents cyclopentyl, benzyl, phenyl, pyridyl, pyrimidyl            or furyl, where the abovementioned ring systems are            optionally mono- or disubstituted by identical or different            substituents selected from the group consisting of nitro,            fluorine, chlorine, —SO₃H, straight-chain or branched alkoxy            having up to 3 carbon atoms, hydroxyl, or by a radical of            the formula —SO₂—NR⁴⁴R⁴⁵,            -   in which            -   R⁴⁴ and R⁴⁵ have the meanings of R¹⁸ and R¹⁹ given above                and are identical to or different from them,

    -   or

    -   E represents radicals of the formulae

-   -   -   and the heterocycles listed under R³ and R⁴, which are            formed together with the nitrogen atom, are optionally mono-            to trisubstituted, optionally also geminally, by identical            or different substituents selected from the group consisting            of hydroxyl, formyl, carboxyl, straight-chain or branched            acyl or alkoxycarbonyl having in each case up to 3 carbon            atoms, or groups of the formulae —P(O)(OR⁴⁶)(OR⁴⁷),

-   -   -   in which        -   R⁴⁶ and R⁴⁷ have the meanings of R¹⁰ and R¹¹ given above and            are identical to or different from them,        -   R⁴⁸ represents hydroxyl or methoxy,        -   j represents a number 0 or 1,        -   and        -   R⁴⁹ and R⁵⁰ are identical or different and have the meanings            of R¹⁴ and R¹⁵ given above,        -   and/or the heterocycles listed under R³ and R⁴, which are            formed together with the nitrogen atom, are optionally            substituted by straight-chain or branched alkyl having up to            4 carbon atoms which is optionally mono- to trisubstituted            by identical or different substituents selected from the            group consisting of hydroxyl, fluorine, chlorine, carboxyl,            cyclopropyl, cycloheptyl, straight-chain or branched alkoxy            or alkoxycarbonyl having in each case up to 3 carbon atoms,            or by a radical of the formula —SO₃H, —NR⁵¹R⁵² or            P(O)OR⁵³OR⁵⁴,        -   in which        -   R⁵¹ and R⁵² are identical or different and each represents            hydrogen, phenyl, carboxyl, benzyl or straight-chain or            branched alkyl or alkoxy having in each case up to 3 carbon            atoms,        -   R⁵³ and R⁵⁴ are identical or different and have the meanings            of R¹⁰ and R¹¹ given above,        -   and/or the alkyl is optionally substituted by phenyl which            for its part may be mono- to disubstituted by identical or            different substituents selected from the group consisting of            fluorine, chlorine, hydroxyl, methoxy, or by a group of the            formula —NR^(51′)R^(52′),        -   in which        -   R^(51′) and R^(52′) have the meanings of R⁵¹ and R⁵² given            above and are identical to or different from them,        -   and/or the heterocycles listed under R³ and R⁴, which are            formed together with the nitrogen atom, are optionally            substituted by phenyl, pyridyl, piperidinyl, pyrrolidinyl or            tetrazolyl, if appropriate also attached via a nitrogen            function, where the ring systems for their part may be            substituted by hydroxyl or by straight-chain or branched            alkyl or alkoxy having in each case up to 3 carbon atoms,

    -   or

    -   R³ and R⁴ together with the nitrogen atom form radicals of the        formulae

-   -   R⁵ and R⁶ are identical or different and each represents        hydrogen, hydroxyl or represents straight-chain or branched        alkoxy having up to 3 carbon atoms,    -   and their salts, N-oxides, hydrates and isomeric forms.

Very particular preference is given to compounds of the general formula(I),

in which

-   R¹ represents methyl or ethyl,-   R² represents ethyl or propyl,-   R³ and R⁴ are identical or different and each represents a    straight-chain or branched alkyl chain having up to 5 carbon atoms    which is optionally substituted up to two times by identical or    different substituents selected from the group consisting of    hydroxyl and methoxy,    -   or    -   R³ and R⁴ together with the nitrogen atom form a piperidinyl,        morpholinyl, thiomorpholinyl ring, or a radical of the formula

-   -   -   in which        -   R³⁷ represents hydrogen, formyl, straight-chain or branched            acyl or alkoxycarbonyl having in each case up to 3 carbon            atoms, or represents straight-chain or branched alkyl having            up to 3 carbon atoms which is optionally mono- or            disubstituted by identical or different substituents            selected from the group consisting of hydroxyl, carboxyl,            straight-chain or branched alkoxy or alkoxycarbonyl having            in each case up to 3 carbon atoms, or by groups of the            formulae -(D)_(f)NR³⁸R³⁹ or —P(O)(OR⁴²)(OR⁴³),            -   in which            -   f represents a number 0 or 1,            -   D represents a group of the formula —CO,            -   R³⁸ and R³⁹ are identical or different and each                represents hydrogen or methyl,            -   R⁴² and R⁴³ are identical or different and each                represents hydrogen, methyl or ethyl,        -   or        -   R³⁷ represents cyclopentyl,        -   and the heterocycles listed under R³ and R⁴, which are            formed together with the nitrogen atom, are optionally mono-            or disubstituted, optionally also geminally, by identical or            different substituents selected from the group consisting of            hydroxyl, formyl, carboxyl, straight-chain or branched acyl            or alkoxycarbonyl having in each case up to 3 carbon atoms,            or groups of the formulae —P(O)(OR⁴⁶)(OR⁴⁷) or            —(CO)_(i)NR⁴⁹R⁵⁰,        -   in which        -   R⁴⁶ and R⁴⁷ are identical or different and each represents            hydrogen, methyl or ethyl,        -   j represents a number 0 or 1, and        -   R⁴⁹ and R⁵⁰ are identical or different and each represents            hydrogen or methyl        -   and/or the heterocycles listed under R³ and R⁴, which are            formed together with the nitrogen atom, are optionally            substituted by straight-chain or branched alkyl having up to            3 carbon atoms which is optionally mono- or disubstituted by            identical or different substituents selected from the group            consisting of hydroxyl, carboxyl, or by a radical of the            formula P(O)OR⁵³OR⁵⁴,        -   in which        -   R⁵³ and R⁵⁴ are identical or different and each represents            hydrogen, methyl or ethyl,        -   and/or the heterocycles listed under R³ and R⁴, which are            formed together with the nitrogen atom, are optionally            substituted by pyrrolidinyl or piperidinyl attached via            nitrogen,

    -   R⁵ represents hydrogen,

    -   and

    -   R⁶ represents ethoxy or propoxy,

    -   and their salts, hydrates, N-oxides and isomeric forms.

Likewise, very particular preference is given to those compounds of thegeneral formula (I) according to the invention in which R⁵ representshydrogen and the radicals R and —SO₂NR³R⁴ are in a position para to oneanother at the phenyl ring.

Particularly preferred compounds are listed in Table A.

TABLE A Structure

The invention furthermore provides a process for preparing the compoundsof the general formula (I) according to the invention, characterized inthat

-   -   initially compounds of the general formula (II)

-   -   in which    -   R¹ and R² are each as defined above and    -   L represents straight-chain or branched alkyl having up to 4        carbon atoms,    -   are converted with compounds of the general formula (III)

-   -   in which    -   R⁵ and R⁶ are each as defined above,    -   in a two-step reaction in the systems ethanol and phosphorus        oxytrichloride/dichloroethane into the compounds of the general        formula (IV)

-   -   in which    -   R¹, R², R⁵ and R⁶ are each as defined above,    -   which are reacted in a further step with chlorosulphonic acid to        give the compounds of the general formula (V)

-   -   in which    -   R¹, R², R⁵ and R⁶ are each as defined above,    -   which are finally reacted with amines of the general formula        (VI)

HN³R⁴  (VI)

-   -   in which    -   R³ and R⁴ are each as defined above,    -   in inert solvents.

The process according to the invention can be illustrated using thefollowing scheme as an example:

Solvents which are suitable for the individual steps are the customaryorganic solvents which do not change under the reaction conditions.These preferably include ethers, such as diethyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such asbenzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions,or halogenated hydrocarbons, such as dichloromethane, trichloromethane,carbon tetrachloride, dichloroethane, trichloroethylene orchlorobenzene, or ethyl acetate, dimethylformamide, hexamethylphosphorictriamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is alsopossible to use mixtures of the abovementioned solvents. Particularpreference is given to ethanol for the first step and dichloroethane forthe second step.

The reaction temperature can generally be varied within a relativelywide range. In general, the reaction is carried out in a range of from−20° C. to 200° C., preferably of from 0° C. to 70° C.

The process steps according to the invention are generally carried outunder atmospheric pressure. However, it is also possible to operateunder superatmospheric pressure or under reduced pressure (for example,in a range of from 0.5 to 5 bar).

The reaction to give the compounds of the general formula (V) is carriedout in a temperature range of from 0° C. to room temperature, and atatmospheric pressure.

The reaction with the amines of the general formula (VI) is carried outin one of the abovementioned chlorinated halogens, preferably indichloromethane.

The reaction temperature can generally be varied within a relativelywide range. In general, the reaction is carried out at temperatures in arange of from −20° C. to 200° C., preferably of from 0° C. to roomtemperature.

The reaction is generally carried out at atmospheric pressure. However,it is also possible to operate under superatmospheric pressure or underreduced pressure (for example in a range of from 0.5 to 5 bar).

Some of the compounds of the general formula (II) are known, or they arenovel, and they can then be prepared by converting compounds of thegeneral formula (VII)

R²—CO-T  (VII)

in whichR² is as defined aboveandT represents halogen, preferably chlorine,initially by reaction with compounds of the general formula (VIII)

in whichR¹ is as defined abovein inert solvents, if appropriate in the presence of a base andtrimethylsilyl chloride, into the compounds of the general formula (IX)

in whichR¹ and R² are each as defined above,and finally reacting with the compound of the formula (X)

in which L is as defined above,in inert solvents, if appropriate in the presence of a base.

Suitable solvents for the individual steps of the process are thecustomary organic solvents which do not change under the reactionconditions. These preferably include ethers, such as diethyl ether,dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, suchas benzene, toluene, xylene, hexane, cyclohexane or mineral oilfractions, or halogenated hydrocarbons, such as dichloromethane,trichloromethane, carbon tetrachloride, dichloroethylene,trichloroethylene or chlorobenzene, or ethyl acetate, dimethylformamide,hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane orpyridine. It is also possible to use mixtures of the abovementionedsolvents. Particular preference is given to dichloromethane for thefirst step and to a mixture of tetrahydrofuran and pyridine for thesecond step.

Suitable bases are generally alkali metal hydrides or alkali metalalkoxides, such as, for example, sodium hydride or potassiumtert-butoxide, or cyclic amines, such as, for example, piperidine,pyridine, dimethylaminopyridine or C₁-C₄ alkylamines, such as, forexample, triethylamine. Preference is given to triethylamine, pyridineand/or dimethylaminopyridine.

The base is generally employed in an amount of from 1 mol to 4 mol,preferably from 1.2 mol to 3 mol, in each case based on 1 mol of thecompound of the formula (X).

The reaction temperature can generally be varied within a relativelywide range. In general, the reaction is carried out in a range of from−20° C. to 200° C., preferably of from 0° C. to 100° C.

The compounds of the general formulae (VII), (VIII), (IX) and (X) areknown per se, or they can be prepared by customary methods.

The compounds of the general formula (III) can be prepared by

reacting compounds of the general formula (XI)

in whichR⁵ and R⁶ are each as defined abovewith ammonium chloride in toluene and in the presence oftrimethylaluminium in hexane in a temperature range of from −20° C. toroom temperature, preferably at 0° C. and atmospheric pressure, andreacting the resulting amidine, if appropriate in situ, with hydrazinehydrate.

The compounds of the general formula (XI) are known per se, or they canbe prepared by customary methods.

Some of the compounds of the general formula (IV) are known, or they arenovel, in which case they can be prepared by known methods [cf. David R.Marshall, Chemistry and Industry, 2 May 1983, 331-335].

Compounds of the general formula (V) are novel per se, however, they canbe prepared from the compounds of the general formula (IV) in accordancewith the publication Organikum, VEB Deutscher Verlag der Wissenschaften,Berlin 1974, pages 338-339.

The compounds of the general formula (I) according to the invention havean unforeseeable useful pharmacological activity spectrum.

They inhibit either one or more of the cGMP-metabolizingphosphodiesterases (PDE I, PDE II and PDE V). This results in anincrease of cGMP. The differentiated expression of thephosphodiesterases in different cells, tissues and organs, as well asthe differentiated subcellular localization of these enzymes, incombination with the selective inhibitors according to the inventionmake it possible to selectively address the various cGMP-regulatedprocesses.

Moreover, the compounds according to the invention enhance the activityof substances such as, for example EDRF (endothelium derived relaxingfactor), ANP (atrial natriuretic peptide), of nitrovasodilators and allother substances which increase the cGMP concentration in a mannerdifferent from that of phosphodiesterase inhibitors.

They can therefore be employed in pharmaceuticals for treatingcardiovascular disorders, such as, for example, for treatinghypertension, neuronal hypertonia, stable and unstable angina,peripheral and cardial vascularpathies, arrhythmiae, for treatingthromboembolic disorders and ischaemias such as myocardial infarction,stroke, transistory and ischaemic attacks, angina pectoris, obstructionof peripheral circulation, prevention of restenoses after thrombolysistherapy, percutaneous transluminal angioplasty (PTA), percutaneoustransluminal coronary angioplasties (PTCA) and bypass. Furthermore, theymay also be of significance for cerebrovascular disorders. Owing totheir relaxing action on smooth muscles, they are suitable for treatingdisorders of the urogenital system such as hypertrophy of the prostate,incontinence and in particular for treating erectile dysfunction andfemale sexual dysfunction.

Activity of the Phosphodiesterases (PDEs)

The cGMP-stimulated PDE II, the cGMP-inhibited PDE HI and thecAMP-specific PDE IV were isolated either from porcine or bovine heartmyocardium. The Ca²⁺-calmodulin-stimulated PDE I was isolated fromporcine aorta, porcine brain or, preferably, from bovine aorta. ThecGMP-specific PDE V was obtained from porcine small intestine, porcineaorta, human platelets and, preferably, from bovine aorta. Purificationwas carried out by anion exchange chromatography over MonoQ® Pharmacia,essentially following the method of M. Hoey and Miles D. Houslay,Biochemical Pharmacology, Vol. 40, 193-202 (1990) and C. Lugman et al.,Biochemical Pharmacology, Vol. 35, 1743-1751 (1986).

The enzyme activity is determined using a test mixture of 100 ml in 20mM tris/HCl-buffer pH 7.5 containing 5 mM MgCl₂, 0.1 mg/ml of bovineserum albumin and either 800 Bq[³H]cAMP or [³H]cGMP. The finalconcentration of the nucleotides in question is 10⁻⁶ mol/l. The reactionis initiated by addition of the enzyme and the amount of enzyme is suchthat during the incubation time of 30 min, approximately 50% of thesubstrate are converted. To test the cGMP-stimulated PDE II, [³H]cAMP isused as substrate and 10⁻⁶ mol/l of non-labelled cGMP are added to themixture. To test the Ca²⁺-calmodulin-dependent PDE I, 1 mM of CaCl₂ and0.1 mM of calmodulin are added to the reaction mixture. The reaction isquenched by addition of 100 ml of acetonitrile containing 1 mM cAMP and1 mM AMP. 100 ml of the reaction mixture are separated by HPLC, and thecleavage products are determined quantitatively on-line using acontinuous scintillation counter. The substance concentration measuredis the concentration at which the reaction rate is reduced by 50%.Additionally, the “phosphodiesterase [³H] cAMP-SPA enzyme assay” and the“phosphodiesterase [³H] cGMP-SPA enzyme assay” from Amersham LifeScience were used for testing. The test was carried out according to thetest protocol of the manufacturer. To determine the activity of PDE II,the [³H]cAMP SPA assay was used, and 10⁻⁶ M cGMP were added to thereaction mixture to activate the enzyme. To measure PDE I, 10⁻⁷ Mcalmodulin and 1 mM CaCl₂ were added to the reaction mixture. PDE V wasmeasured using the [³H]cGMP SPA assay.

Inhibition of the Phosphodiesterases In Vitro

PDE I PDE II PDE V Ex. No. IC₅₀ [nM] IC₅₀ [nM] IC₅₀ [nM] 16 300 >1000 219 200 >1000 2 20 200 >1000 2 26 100 >1000 1 27 200 >1000 3 32 100 >10004 260 300 >1000 10 275 50 >1000 3 338 200 >1000 5

In principle, inhibition of one or more phosphodiesterases of this typeresults in an increase of the cGMP concentration. Thus, the compoundsare of interest for all therapies in which an increase of the cGMPconcentration is considered to be beneficial.

The cardiovascular effects were investigated using SH-rats and dogs. Thesubstances were administered intravenously or orally.

The erection-stimulating action was investigated using rabbits whichwere awake [Naganuma H, Egashira T, Fuji J, Clinical and ExperimentalPharmacology and Physiology 20, 177-183 (1993)]. The substances wereadministered intravenously, orally or parenterally.

The novel active compounds and their physiologically acceptable salts(for example hydrochlorides, maleates or lactates) can be converted in aknown manner into the customary formulations, such as tablets, coatedtablets, pills, granules, aerosols, syrups, emulsions, suspensions andsolutions, using inert non-toxic, pharmaceutically suitable excipientsor solvents. In this case the therapeutically active compound should ineach case be present in a concentration from approximately 0.5 to 90% byweight of the total mixture, i.e. in amounts which are sufficient inorder to achieve the dosage range indicated.

The formulations are prepared, for example, by extending the activecompounds using solvents and/or excipients, if appropriate usingemulsifiers and/or dispersants, it optionally being possible, forexample, to use organic solvents as auxiliary solvents if the diluentused is water.

Administration is carried out in a customary manner, preferably orally,transdermally or parenterally, for example perlingually, buccally,intravenously, nasally, rectally or inhalatively.

For human use, in the case of oral administration, it is good practiceto administer doses of from 0.001 to 50 mg/kg, preferably of 0.01mg/kg-20 mg/kg. In the case of parenteral administration, such as, forexample, via mucous membranes nasally, buccally or inhalatively, it isgood practice to use doses of 0.001 mg/kg-0.5 mg/kg.

In spite of this, if appropriate it may be necessary to depart from theamounts mentioned, namely depending on the body weight or the type ofadministration route, on the individual response towards the medicament,the manner of its formulation and the time or interval at whichadministration takes place. Thus, in some cases it may be adequate tomanage with less than the abovementioned minimum amounts, while in othercases the upper limit mentioned has to be exceeded. In the case of theadministration of relatively large amounts, it may be advisable todivide these into several individual doses over the course of the day.

The compounds according to the invention are also suitable for use inveterinary medicine. For use in veterinary medicine, the compounds ortheir non-toxic salts can be administered in a suitable formulation inaccordance with general veterinary practice. Depending on the kind ofanimal to be treated, the veterinary surgeon can determine the nature ofuse and the dosage.

Starting Materials EXAMPLE 1A 2-Butyrylaminopropionic acid

22.27 g (250 mmol) of D,L-alanine and 55.66 g (550 mmol) oftriethylamine are dissolved in 250 ml of dichloromethane, and thesolution is cooled to 0° C. 59.75 g (550 mmol) of trimethylsilylchloride are added dropwise, and the solution is stirred for 1 hour atroom temperature and for 1 hour at 40° C. After cooling to −10° C.,26.64 g (250 mmol) of butyryl chloride are added dropwise, and theresulting mixture is stirred for 2 hours at −10° C. and for one hour atroom temperature.

With ice-cooling, 125 ml of water are added dropwise and the reactionmixture is stirred at room temperature for 15 minutes. The aqueous phaseis evaporated to dryness, the residue is titrated with acetone and themother liquor is filtered off with suction. The solvent is removed andthe residue is chromatographed. The resulting product is dissolved in 3Naqueous sodium hydroxide solution and the resulting solution isevaporated to dryness. The residue is taken up in conc. HCl and oncemore evaporated to dryness. The residue is stirred with acetone,precipitated solid is filtered off with suction and the solvent isremoved under reduced pressure. This gives 28.2 g (71%) of a viscous oilwhich crystallizes after some time.

200 MHz ¹H-NMR (DMSO-d6): 0.84, t, 3H, 1.22, d, 3H, 1.50, hex, 2H, 2.07,t, 2H, 4.20, quin., 1H, 8.09, d, 1H.

EXAMPLE 2A 2-Butyrylamino butyric acid

25.78 g of 2-aminobutyric acid (250 mmol) and 55.66 g (550 mmol) oftriethylamine are dissolved in 250 ml of dichloromethane, and thesolution is cooled to 0° C. 59.75 g (550 mmol) of trimethylsilylchloride are added dropwise, and the solution is stirred for 1 hour atroom temperature and for 1 hour at 40° C. After cooling to −10° C.,26.64 g (250 mmol) of butyryl chloride are added dropwise, and theresulting mixture is stirred for 2 hours at −10° C. and for one hour atroom temperature.

With ice-cooling, 125 ml of water are added dropwise, and the reactionmixture is stirred at room temperature for 15 minutes. The organic phaseis admixed with aqueous sodium hydroxide solution and the organicsolvent is removed under reduced pressure. After acidification, theprecipitated solid is stirred once with water and twice with petroleumether and dried at 45° C. under reduced pressure. This gives 29.1 g(67%) of a colourless solid.

200 MHz ¹H-NMR (DMSO-d6): 0.88, 2t, 6H, 1.51, quart., 2H, 1.65, m, 2H,2.09, t, 2H, 4.10, m, 1H, 8.01, d, 1H, 12.25, s, m 1H.

EXAMPLE 3A 2-Ethoxybenzonitrile

25 g (210 mmol) of 2-hydroxybenzonitrile are refluxed with 87 g ofpotassium carbonate and 34.3 g (314.8 mmol) of ethyl bromide in 500 mlof acetone overnight. The solid is filtered off, the solvent is removedunder reduced pressure and the residue is distilled under reducedpressure. This gives 30.0 g (97%) of a colourless liquid.

200 MHz ¹H-NMR (DMSO-d6): 1.48, t, 3H, 4.15, quart., 2H, 6.99, dt, 2H,7.51, dt, 2H.

EXAMPLE 4A 2-Ethoxybenzamidine hydrochloride

21.4 g (400 mmol) of ammonium chloride are suspended in 375 ml oftoluene, and the suspension is cooled to 0° C. 200 ml of a 2M solutionof trimethylaluminium in hexane are added dropwise, and the mixture isstirred at room temperature until the evolution of gas has ceased. Afteraddition of 29.44 g (200 mmol) of 2-ethoxybenzonitrile, the reactionmixture is stirred at 80° C. (bath) overnight.

With ice-cooling, the cooled reaction mixture is added to a suspensionof 100 g of silica gel and 950 ml of chloroform, and the mixture isstirred at room temperature for 30 minutes. The mixture is filtered offwith suction, and the filter residue is washed with the same amount ofmethanol. The mother liquor is concentrated, the resulting residue isstirred with a mixture of dichloromethane and methanol (9:1), the solidis filtered off with suction and the mother liquor is concentrated. Thisgives 30.4 g (76%) of a colourless solid.

200 MHz ¹H-NMR (DMSO-d6): 1.36, t, 3H, 4.12, quart., 2H, 7.10, t, 1H,7.21, d, 1H, 7.52, m, 2H, 9.30, s, broad, 4H.

EXAMPLE 5A 2-Propoxybenzonitrile

75 g (630 ml) of 2-hydroxybenzonitrile are refluxed with 174 g (1.26mol) of potassium carbonate and 232.2 g (1.89 mol) of ethyl bromide in11 of acetone overnight. The solid is filtered off, the solvent isremoved under reduced pressure and the residue is distilled underreduced pressure.

b.p.: 89° C. (0.7 mbar)

Yield: 95.1 g (93.7%)

EXAMPLE 6A 2-Propoxybenzamidine hydrochloride

21.41 g (400 mmol) of ammonium chloride are suspended in 400 ml oftoluene and cooled to 0-5° C. 200 ml of a 2M solution oftriethylaluminium in hexane are added dropwise, and the mixture isstirred at room temperature until the evolution of gas has ceased. Afteraddition of 32.2 g (200 mmol) of 2-propoxybenzonitrile, the reactionmixture is stirred at 80° C. (bath) overnight. With ice-cooling, thecooled reaction mixture is added to a suspension of 300 g of silica geland 2.85 l of ice-cooled chloroform, and the mixture is stirred for 30minutes. The mixture is filtered off with suction and the filter residueis washed with the same amount of methanol. The solvent is distilled offunder reduced pressure, the residue is stirred with 500 ml of a mixtureof dichloromethane and methanol (9:1), the solid is filtered off and themother liquor is concentrated. The residue is stirred with petroleumether and filtered off with suction. This gives 22.3 g (52%) of product.

¹H-NMR (200 MHz, CD₃OD): 1.05 (3H); 1.85 (sex, 2H); 4.1 (A, 2H); 7.0-7.2(m, 2H); 7.5-7.65 (m, 2H).

EXAMPLE 7A 2-Ethoxy-4-methoxybenzonitrile

30.0 g (201 mmol) of 2-hydroxy-4-methoxybenzonitrile are refluxed with83.4 g of potassium carbonate (603 mmol) and 32.88 g (301 mmol) ofbromoethane in 550 ml of acetone for 18 hours. After filtration, thesolvent is removed under reduced pressure and the residue is purified bysilica gel chromatography (cyclohexane:ethyl acetate=10:1): 35.9 g of anoil

R_(f)=0.37 (cyclohexane:ethyl acetate=3:1)

200 MHz ¹H-NMR (CDCl₃): 1.48, t, 3H, 3.85, s, 3H, 4.12, quart., 2H,6.46, m, 2H, 7.48, d, 1H.

EXAMPLE 8A 2-Ethoxy-4-methoxybenzamidine hydrochloride

6.98 g (130 mmol) of ammonium chloride are suspended in 150 ml oftoluene, and the suspension is cooled to 0° C. 70 ml of a 2M solution oftrimethylaluminium in hexane are added dropwise, and the mixture isstirred at room temperature until the evolution of gas has ceased. Afteraddition of 11.56 g (65 mmol) of 2-ethoxy-4-methoxybenzonitrile, thereaction mixture is stirred at 80° C. (bath) overnight.

With ice-cooling, the cooled reaction mixture is added to a suspensionof 100 g of silica gel and 950 ml of dichloromethane, and the mixture isstirred at room temperature for 30 minutes. The mixture is filtered offwith suction and the filter residue is washed with the same amount ofmethanol. The mother liquor is concentrated, the resulting residue isstirred with a mixture of dichloromethane and methanol (9:1), the solidis filtered off with suction and the mother liquor is concentrated. Theresidue is stirred with petroleum ether and filtered off with suction.This gives 7.95 g (50%) of a solid.

200 MHz ¹H-NMR (DMSO-d6): 1.36, t, 3H, 3.84, s, 3H, 4.15, quart., 2H,6.71, m, 2H, 7.53, d, 1H, 8.91, s, broad, 3H.

EXAMPLE 9A2-(2-Ethoxyphenyl)-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

24.4 g (0.186 mol) of N-acetyl-D,L-alanine are initially charged in 200ml of absolute tetrahydrofuran, and 45 ml of absolute pyridine and 0.5 gof 4-dimethylaminopyridine are added. The mixture is heated to reflux,and 51.85 g (0.372 mol) of ethyl oxalyl chloride are added dropwise. Themixture is heated under reflux for a further 90 minutes, cooled, pouredinto ice-water and extracted three times with ethyl acetate. The organicphase is dried over sodium sulphate, concentrated and taken up in 62.5ml of methanol. 9 g of sodium bicarbonate are added and the mixture isstirred under reflux for 2.5 hours and filtered.

With ice-cooling, 9.54 g (190.65 mmol) of hydrazine hydrate are addeddropwise to a solution of 38.26 g (190.65 mmol) of2-ethoxy-4-methoxybenzamidine hydrochloride in 250 ml of methanol, andthe resulting suspension is stirred at room temperature for another 30minutes. The methanolic solution described above is added to thisreaction mixture, and the mixture is stirred at a bath temperature of70° C. for 4 hours. After filtration, the mixture is concentrated, theresidue is partitioned between dichloromethane and water, the organicphase is dried over sodium sulphate and the solvent is removed underreduced pressure.

The residue is taken up in 250 ml of 1,2-dichloroethane, 32.1 ml (348mmol) of phosphorus oxychloride are added dropwise and the mixture isheated under reflux for two hours. The mixture is cooled, concentrated,taken up in a little methylene chloride and admixed with diethyl ether,and the solid is filtered off with suction. After the silica gelchromatography (methylene chloride/methanol 95:5), the solution isconcentrated and the crystalline residue is stirred with diethyl ether.

Yield: 8.1 g (14.9% of theory)

200 MHz ¹H-NMR (CDCl₃): 1.58, t, 3H, 2.62, s, 3H, 2.68, s, 3H, 4.25, q,2H, 7.04, d, 1H; 7.12, t, 1H; 7.5, dt, 1H; 8.19, dd, 1H; 10.02, s, 1H.

EXAMPLE 10A2-(2-Ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

7.16 g (45 mmol) of 2-butyrylamino-propionic acid and 10.67 g ofpyridine are dissolved in 45 ml of THF and, after addition of a spatulatip of DMAP, heated to reflux. 12.29 g (90 mmol) of ethyl oxalylchloride are slowly added dropwise, and the reaction mixture is refluxedfor 3 hours. The mixture is poured into ice-water and extracted threetimes with ethyl acetate and the organic phase is dried over sodiumsulphate and concentrated using a rotary evaporator. The residue istaken up in 15 ml of ethanol and refluxed with 2.15 g of sodiumbicarbonate for 2.5 hours. The cooled solution is filtered.

With ice-cooling, 2.25 g (45 mmol) of hydrazine hydrate are addeddropwise to a solution of 9.03 g (45 mmol) of 2-ethoxybenzamidinehydrochloride in 45 ml of ethanol, and the resulting suspension isstirred at room temperature for another 10 minutes. The ethanolicsolution described above is added to this reaction mixture, and themixture is stirred at a bath temperature of 70° C. for 4 hours. Afterfiltration, the mixture is concentrated, the residue is partitionedbetween dichloromethane and water, the organic phase is dried oversodium sulphate and the solvent is removed under reduced pressure.

This residue is dissolved in 60 ml of 1,2-dichloroethane and, afteraddition of 7.5 ml of phosphorus oxychloride, refluxed for 2 hours. Themixture is diluted with dichloromethane and neutralized by addition ofsodium bicarbonate solution and solid sodium bicarbonate. The organicphase is dried and the solvent is removed under reduced pressure.Chromatography using ethyl acetate and crystallization afford 4.00 g(28%) of a colourless solid, R_(f) 0.42 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.56, t, 3H, 1.89, hex, 2H, 2.67,s, 3H, 3.00, t, 2H, 4.26, quart., 2H, 7.05, m, 2H, 7.50, dt, 1H, 8.17,dd, 1H, 10.00, s, 1H.

EXAMPLE 11A2-(2-Propoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

7.16 g (45 mmol) of 2-butyrylaminopropionic acid and 10.67 g of pyridineare dissolved in 45 ml of tetrahydrofuran and, after addition of aspatula tip of dimethylaminopyridine, heated to reflux. 12.29 g (90mmol) of ethyl oxalyl chloride are slowly added dropwise, and thereaction mixture is refluxed for 3 hours. The mixture is poured intoice-water and extracted three times with ethyl acetate, and the organicphase is dried over sodium sulphate and concentrated using a rotaryevaporator. The residue is taken up in 15 ml of ethanol and refluxedwith 2.15 g of sodium bicarbonate for 2.5 hours. The cooled solution isfiltered.

With ice-cooling, 2.25 g (45 mmol) of hydrazine hydrate are addeddropwise to a solution of 9.66 g (45 mmol) of 2-propoxybenzamidinehydrochloride in 45 ml of ethanol, and the resulting suspension isstirred at room temperature for another 10 minutes. The ethanolicsolution described above is added to this reaction mixture, and themixture is stirred at a bath temperature of 70° C. for 4 hours. Afterfiltration, the mixture is concentrated, the residue is partitionedbetween dichloromethane and water, the organic phase is dried oversodium sulphate and the solvent is reduced under reduced pressure.

This residue is dissolved in 60 ml of 1,2-dichloroethane and, afteraddition of 7.5 ml of phosphorus oxychloride, refluxed for 2 hours. Themixture is diluted with dichloromethane and neutralized by addition ofsodium bicarbonate solution and solid sodium bicarbonate. The organicphase is dried and the solvent is removed under reduced pressure.Crystallization from ethyl acetate gives 2.85 g (19.1%) of a yellowsolid, chromatographic purification of the mother liquor gives a further1.25 g (8.4%) of the product. R_(f)=0.45 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.03, t, 3H, 1.15, t, 3H, 1.92, m, 4H, 2.67, s,3H, 3.01, t, 2H, 4.17, t, 2H, 7.09, m, 2H, 7.50, dt, 1H, 8.17, dd, 1H,10.02, s, 1H.

EXAMPLE 12A2-(2-Ethoxy-4-methoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-j][1,2,4]triazin-4-one

5.50 g (34.8 mmol) of 2-butyrylaminopropionic acid and 8.19 g ofpyridine are dissolved in 35 ml of tetrahydrofuran and, after additionof a spatula tip of dimethylaminopyridine, heated to reflux. 9.43 g (69mmol) of ethyl oxalyl chloride are slowly added dropwise, and thereaction mixture is refluxed for 3 hours. The mixture is poured intoice-water and extracted three times with ethyl acetate, and the organicphase is dried over sodium sulphate and concentrated using a rotaryevaporator. The residue is taken up in 11 ml of methanol and refluxedwith 1.65 g of sodium bicarbonate for 2.5 hours. The cooled solution isfiltered.

With ice-cooling, 1.73 g (34.5 mmol) of hydrazine hydrate are addeddropwise to a solution of 7.95 g (34.5 mmol) of2-ethoxy-4-methoxybenzamidine hydrochloride in 35 ml of ethanol, and theresulting suspension is stirred at room temperature for another 30minutes. The methanolic solution described above is added to thisreaction mixture, and the mixture is stirred at a bath temperature of70° C. for 4 hours. After filtration, the mixture is concentrated, theresidue is partitioned between dichloromethane and water, the organicphase is dried over sodium sulphate and the solvent is removed underreduced pressure.

This residue is dissolved in 46 ml of 1,2-dichloroethane and, afteraddition of 5.74 ml of phosphorus oxychloride, refluxed for 2 hours. Themixture is diluted with dichloromethane and neutralized by addition ofsodium bicarbonate solution and solid sodium bicarbonate. The organicphase is dried and the solvent is removed under reduced pressure.Chromatography (dichloromethane:methanol=50:1) gives 0.31 g (2.5%) of asolid.

R_(f)=0.46 (dichloromethane:methanol=20:1)

200 MHz ¹H-NMR (CDCl₃): 1.03, t, 3H, 1.58, t, 3H, 1.88, m, 2H, 2.62, s,3H, 2.98, t, 2H, 3.89, s, 3H, 4.25, quart., 2H, 6.54, d, 1H, 6.67, dd,1H, 8.14, d, 1H; 9.54, s, 1H.

EXAMPLE 13A2-(2-Ethoxyphenyl)-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

29.06 g (167.8 mmol) of 2-butyrylaminobutyric acid and 39.76 g ofpyridine are dissolved in 170 ml of tetrahydrofuran and, after additionof a spatula tip of dimethylaminopyridine, heated to reflux. 45.81 g(335.5 mmol) of ethyl oxalyl chloride are slowly added dropwise, and thereaction mixture is refluxed for 3 hours. The mixture is poured intoice-water and extracted three times with ethyl acetate, and the organicphase is dried over sodium sulphate and concentrated using a rotaryevaporator. The residue is taken up in 15 ml of methanol, and half ofthe solution is refluxed with 7.96 g of sodium bicarbonate for 2.5hours. The cooled solution is filtered.

With ice-cooling, 4.20 g (83.9 mmol) of hydrazine hydrate are addeddropwise to a solution of 16.83 g (83.9 mmol) of 2-ethoxybenzamidinehydrochloride in 85 ml of ethanol, and the resulting suspension isstirred at room temperature for another 10 minutes. The methanolicsolution described above is added to this reaction mixture, and themixture is stirred at a bath temperature of 70° C. for 4 hours. Afterfiltration, the mixture is concentrated, the residue is partitionedbetween dichloromethane and water, the organic phase is dried oversodium sulphate and the solvent is removed under reduced pressure.

This residue is dissolved in 112 ml of 1,2-dichloroethane and, afteraddition of 1.4 ml of phosphorus oxychloride, refluxed for 2 hours. Themixture is diluted with dichloromethane and neutralized by addition ofsodium bicarbonate solution and solid sodium bicarbonate. The organicphase is dried and the solvent is removed under reduced pressure.Chromatography (dichloromethane:methanol=50:1) gives 3.69 g (12.4%) of acolourless solid, R_(f)=0.46 (dichloromethane:methanol=20:1)

200 MHz ¹H-NMR (CDCl₃): 1.32, t, 3H, 1.57, t, 3H, 1.94, m, 8H, 3.03,quart., 2H, 3.64, quin., 1H; 4.27, quart., 2H, 7.06, d, 1H; 7.12, t, 1H,7.50, dt, 1H, 8.16, dd, 1H; 9.91, s, 1H.

EXAMPLE 14A4-Ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride

7.25 g (25.5 mmol) of2-(2-ethoxyphenyl)-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-oneare initially charged, and 26.74 g (0.23 mol) of chlorosulphonic acidare added with ice-cooling. The mixture is stirred at room temperatureovernight and poured into ice-water, and the crystals are filtered offwith suction and dried in a vacuum desiccator.

Yield: 9.5 g (97% of theory)

200 MHz ¹H-NMR (d⁶-DMSO): 1.32, t, 3H, 2.63, s, 3H, 2.73, s, 3H, 4.13,q, 2H, 7.15, d, 1H, 7.77, m, 2H, 12.5, s, 1H;

EXAMPLE 15A4-Ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride

At 0° C., 2.00 g (6.4 mmol) of2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare slowly added to 3.83 ml of chlorosulphonic acid. At roomtemperature, the reaction mixture is stirred overnight, and then pouredinto ice-water and extracted with dichloromethane. This gives 2.40 g(91%) of a colourless foam.

200 MHz ¹H-NMR (CDCl₃): 1.03, t, 3H, 1.61, t, 2H, 1.92, hex, 2H, 2.67,s, 3H, 3.10, t, 2H, 4.42, quart., 2H, 7.27, t, 1H; 8.20, dd, 1H, 8.67,d, 1H, 10.18, s, 1H.

EXAMPLE 16A4-Propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride

At 0° C., 2.80 g (8.6 mmol) of2-(2-propoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare added slowly to 5.13 ml of chlorosulphonic acid. The reactionmixture is stirred at room temperature overnight and then poured intoice-water and extracted with dichloromethane. This gives 3.50 g (96%) ofa colourless foam.

R_(f)=0.49 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.03, 2t, 6H, 1.95, m, 4H, 2.81, s, 3H, 3.22, t,2H, 4.11, t, 2H, 7.09, m, 1H, 8.06, dd, 1H, 8.21 m, 1H, 12.0, s, 1H.

EXAMPLE 17A4-Ethoxy-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride

At 0° C., 0.31 g (0.9 mmol) of2-(2-ethoxy-4-methoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-oneare added slowly to 0.54 ml of chlorosulphonic acid. The reactionmixture is stirred at room temperature overnight and then poured intoice-water and extracted with dichloromethane. This gives 0.355 g (89%)of a colourless foam.

R_(f)=0.50 (dichloromethane/methanol=20:1)

200 MHz ¹H-NMR (CDCl₃): 1.05, t, 3H, 1.66, t, 3H, 1.95, m, 2H, 2.61, s,3H, 3.11, t, 2H, 4.15, s, 3H, 4.40, quart., 2H, 6.65, s, 1H, 8.72, s,1H, 9.75, s, 1H.

EXAMPLE 18A4-Ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzene-sulphonylchloride

At 0° C., 1.70 g (5.21 mmol) of2-(2-ethoxy-phenyl)-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare added slowly to 3.12 ml of chlorosulphonic acid. The reactionmixture is stirred at room temperature overnight and then poured intoice-water and extracted with dichloromethane. This gives 2.10 g (94%) ofa colourless foam.

400 MHz ¹H-NMR (CDCl₃): 1.03, t, 3H, 1.35, t, 3H, 1.62, t, 3H, 1.92,sex., 2H, 3.07, quart., 2H, 3.12, t, 2H, 4.42, quart., 2H, 7.38, d, 1H,8.19, dd, 1H, 8.70, d, 11H, 10.08, s, broad, 1H.

EXAMPLE 19A Diethyl (4-piperidinylmethyl)-phosphonate

2.11 g (528 mmol) of 60% strength sodium hydride are initially chargedin 50 ml of absolute tetrahydrofuran, and 15.7 g (52.8 mmol) of diethylmethanediphosphonate are added dropwise. The mixture is stirred at roomtemperature for another 30 minutes, and 10.1 g (52.8 mmol) of1-benzyl-4-piperidone are then added. The mixture is stirred for onehour at room temperature and for one hour under reflux, concentrated,admixed with water and extracted three times with dichloromethane, andthe organic phases are dried over sodium sulphate and concentrated. Theresidue is hydrogenated in 50 ml of ethanol over 1.7 g of 10%palladium-carbon at room temperature and 3 bar. The catalyst is filteredoff with suction and the filtrate is concentrated.

Yield: 12.5 g (100% of theory)

400 MHz, ¹H-NMR (CDCl₃): 1.13, m, 2H, 1.32, t, 6H, 1.69, dd, 2H,1.74-1.95, m, 4H, 2.62, dt, 2H, 3.05, m, 2H, 4.1, m, 4H.

EXAMPLE 20A 5-Methyl-4-furoxanecarbaldehyde

40 g (571 mmol) of crotonaldehyde are dissolved in 80 ml of acetic acidand, at 0° C., admixed dropwise with a solution of 137 g (1.99 mol) ofsodium nitrite in 300 ml of water. The mixture is stirred at roomtemperature for 2 hours, diluted with 800 ml of water and extracted 3times with dichloromethane. The organic phase is dried, andchromatography (cyclohexane/ethyl acetate) gives 13.8 g (18.9%) of5-methyl-4-furoxanecarbaldehyde.

200 MHz ¹H-NMR (CDCl₃): 2.39, s, 3H, 10.10, s, 1H.

EXAMPLE 21A 5-Methyl-4-furoxanecarbonyl chloride

13.5 g (105 mmol) of 5-methyl-4-furoxanecarbaldehyde are dissolved in200 ml of acetone and, at 0° C., admixed dropwise with a solution of16.86 g (168 mmol) of chromium trioxide in 120 ml of a 2.2M sulphuricacid. The mixture is stirred at 10-15° C. for 2 hours and then at roomtemperature overnight. With cooling, 100 ml of isopropanol are addeddropwise and, after 30 minutes, the solvent is removed under reducedpressure. The aqueous phase is extracted 3 times with ether, the organicphase is dried over magnesium sulphate and the solvent is removed underreduced pressure. The residue is dissolved in 1M sodium hydroxidesolution and the solution is extracted 3 times with ether. The aqueousphase is acidified and extracted 3 times with ether. The organic phaseis dried and the solvent is removed under reduced pressure. The residueis stirred with petroleum ether and filtered off with suction.

6.92 g of the residue are refluxed with 10 ml of thionyl chloride in 20ml of dichloromethane for 6 hours. The mixture is diluted with toluene,filtered and concentrated using a rotary evaporator. The residue is oncemore taken up in dichloromethane, admixed with 10 ml of thionyl chlorideand refluxed for 48 hours. The solvent is removed under reduced pressureand the residue is distilled under reduced pressure. This gives 2.00 g(25%) of colourless crystals.

200 MHz ¹H-NMR (CDCl₃): 2.41, s.

EXAMPLE 22A1-(5-Methyl-4-furoxanecarbonyl)-4-tert-butyl-oxycarbonyl-piperazine

2.75 g (14.7 mmol) of Boc-piperazine and 1.49 g of triethylamine aredissolved in 20 ml of dichloromethane and, at 0° C., admixed a little ata time with 2.00 g (12.3 mmol) of 5-methyl-4-furoxanecarbonyl chloride.The mixture is stirred for 30 minutes at 0° C. and for 2 hours at roomtemperature, diluted with dichloromethane and washed with water. Thesolvent is removed under reduced pressure and the residue is purified bychromatography (cyclohexane/ethyl acetate). This gives 3.33 g (87%) of1-(5-methyl-4-furoxanecarbonyl)-4-tert-butyl-oxycarbonyl-piperazine.

200 MHz ¹H-NMR (CDCl₃): 1.50, s, 9H, 2.30, s, 3H, 3.55, m, 4H, 3.78, m,2H, 3.87, m, 2H.

EXAMPLE 23A 1-(5-Methyl-4-furoxanecarbonyl)-piperazine trifluoroacetate

3.12 g (10 mmol) of1-(5-methyl-4-furoxanecarbonyl)-4-tert-butyl-oxycarbonyl-piperazine aredissolved in 20 ml of dichloromethane and, at 0° C., admixed with 2 mlof trifluoroacetic acid. The mixture is allowed to warm to roomtemperature and stirred for 72 hours. After addition of 10 ml of ether,the precipitate is filtered off with suction and dried. This gives 2.47g (83%) of 1-(5-methyl-4-furoxanecarbonyl)-piperazine trifluoroacetate.

200 MHz ¹H-NMR (DMSO-d₆): 2.18, s, 3H, 3.18, m, 2H, 3.25, m, 2H, 3.83,m, 2H, 3.90, m, 2H, 8.89, s, broad, 2H.

PREPARATION EXAMPLES Example 12-[2-Ethoxy-5-(4-methyl-piperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one

0.1 g (0.26 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride are dissolved in 10 ml of dichloromethane and cooled to 0° C.After addition of a spatula tip of DMAP, 80 mg (0.784 mmol) ofN-methylpiperazine are added and the reaction mixture is stirred at roomtemperature overnight. The mixture is diluted with dichloromethane, theorganic phase is washed with ammonium chloride solution and dried oversodium sulphate and the solvent is removed under reduced pressure. Theresidue is chromatographed over silica gel (dichloromethane/methanol9:1).

Yield: 40 mg (34.5% of theory)

Mass spectrum: 447 (M+H); 284; 256; 224.

Example 22-[2-Ethoxy-5-(4-hydroxyethylpiperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.261 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 100 mg (0.784 mmol) of 4-hydroxypiperazine, 45 mg (36.1% oftheory) of2-[2-ethoxy-5-(4-hydroxy-ethylpiperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-oneare obtained.

Mass spectrum: 477 (M+H); 284; 256; 239.

Example 32-[2-Ethoxy-5-(4-hydroxypiperidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.261 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 80 mg (0.784 mmol) of 4-hydroxypiperidine, 35 mg (29.8% oftheory) of2-[2-ethoxy-5-(4-hydroxy-piperidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-oneare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.61, t, 3H, 1.69, m, 2H, 1.94, m, 2H, 2.67, s,3H, 2.70, s, 3H, 3.02, m, 2H, 3.30, m, 2H, 3.84, m, 1H, 4.37, q, 2H,7.18, d, 1H, 7.90, dd, 1H, 8.52, d, 1H, 9.73, s, 1H.

Example 42-[2-Ethoxy-5-(4-hydroxymethylpiperidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.261 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 90 mg (0.784 mmol) of 4-hydroxymethylpiperidine, 22 mg (18%of theory) of2-[2-ethoxy-5-(4-hydroxy-methylpiperidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.38, dt, 2H, 1.62, t, 3H, 1.82, dd, 2H, 2.35,dt, 2H, 2.78, s, 3H, 2.84, s, 3H, 3.5, d, 2H, 3.87, d, 2H, 4.39, q, 2H,7.21, d, 1H, 7.95, dd, 1H, 8.51, d, 1H, 10.03, bs, 1H.

Example 52-[2-Ethoxy-5-(3-hydroxypyrrolidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.261 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 70 mg (0.784 mmol) of 3-hydroxypyrrolidine, 13 mg (11.1% oftheory) of2-[2-ethoxy-5-(3-hydroxy-pyrrolidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-oneare obtained.

Mass spectrum: 434 (M+H)

Example 64-Ethoxy-N-ethyl-N-(2-hydroxyethyl)-3-(5,7-dimethyl-4-oxo-3,4-dihydro-imidazo[5,1-f]-[1,2,4]triazin-2-yl)benzenesulphonamide

By the same method, starting with 100 mg (0.261 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 70 mg (0.784 mmol) of 2-(ethylamino)-ethanol, 23 mg (20.1%of theory) of4-ethoxy-N-ethyl-N-(2-hydroxyethyl)-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo-[5,1-f][1,2,4]triazin-2-yl)-benzene-sulphonamideare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.2, t, 3H, 1.6, t, 3H, 2.17, bs, 1H, 2.69, s,3H, 2.75, s, 3H, 3.33, m, 4H, 3.8, t, 2H, 4.36, q, 2H, 7.18, d, 1H,7.99, dd, 1H, 8.6, d, 1H, 9.84, bs, 1H.

Example 7N,N-Diethyl-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonamide

By the same method, starting with 100 mg (0.261 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzene-sulphonylchloride and 60 mg (0.784 mmol) of diethylamine, 21 mg (18.6% of theory)ofN,N-diethyl-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonamideare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.18, t, 6H, 1.61, t, 3H, 2.68, s, 3H, 2.72, s,3H, 3.29, q, 4H, 4.35, q, 2H, 7.15, d, 1H, 7.95, dd, 1H, 8.58, d, 1H,9.8, bs, 1H.

Example 82-[2-Ethoxy-5-(4-(2-pyrimidinyl)-piperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.261 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 130 mg (0.784 mmol) of 1-(2-pyrimidinyl)-piperazine, 38 mg(28.2% of theory) of2-[2-ethoxy-5-(4-(2-pyrimidinyl)-piperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-oneare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.6, t, 3H, 2.68, s, 3H, 2.72, s, 3H, 3.12, t,4H, 3.96, t, 4H, 4.34, q, 2H, 6.5, t, 1H, 7.18, d, 1H, 7.9, dd, 1H,8.28, d, 2H, 8.51, d, 1H; 9.7, bs, 1H.

Example 92-[2-Ethoxy-5-(morpholine-4-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.261 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 70 mg (0.784 mmol) of morpholine, 28 mg (24.2% of theory)of2-[2-ethoxy-5-(morpholine-4-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.53, t, 3H, 2.69, s, 3H, 2.72, s, 3H, 3.06, t,4H, 3.77, t, 4H, 4.39, q, 2H, 7.2, d, 1H, 7.91, dd, 1H, 8.51, d, 1H,9.78, bs, 1H.

Example 102-[2-Ethoxy-5-(1,4-dioxa-6-azaspiro[4.4]nonane-6-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.261 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 100 mg (0.784 mmol) of 1,4-dioxa-6-azaspiro[4.4]nonane, 45mg (35.3% of theory) of2-[2-ethoxy-5-(1,4-dioxa-6-azaspiro[4.4]nonane-6-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one.

200 MHz ¹H-NMR (CDCl₃): 1.58, t, 3H, 2.02, t, 2H, 2.61, s, 3H, 2.65, s,3H, 3.32, s, 2H, 3.41, t, 2H, 3.88, m, 4H, 4.34, q, 2H, 7.17, d, 1H,7.92, dd, 1H, 8.51, d, 1H, 9.92, bs, 1H.

Example 11N,N-Bis-(2-methoxyethyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydro-imidazo[5,1-]-[1,2,4]triazin-2-yl)-benzenesulphonamide

By the same method, starting with 100 mg (0.261 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzene-sulphonylchloride and 100 mg (0.784 mmol) of bis-(2-methoxyethyl)-amine, 37 mg(27.5% of theory) ofN,N-bis-(2-methoxy-ethyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonamideare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.58, t, 3H, 2.61, s, 3H, 2.64, s, 3H, 3.3, s,6H, 3.46, t, 4H, 3.56, t, 4H, 4.32, q, 2H, 7.12, d, 1H, 7.95, dd, 1H,8.51, d, 1H, 9.9, bs, 1H

Example 12N-(3-Isoxazolyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonamide

By the same method, starting with 100 mg (0.261 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 70 mg (0.784 mmol) of 3-aminoisoxazol, 20 mg (17.2% oftheory)N-(3-isoxazolyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonamideare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.6, t, 3H, 2.73, s, 3H, 2.81, s, 3H, 4.35, q,2H, 6.6, d, 1H, 7.14, d, 1H, 8.05, dd, 1H, 8.27, d, 1H, 8.63, d, 1H,9.61, bs, 1H.

Example 132-[2-Ethoxy-5-(2-t-butoxycarbonylaminomethylmorpholine-4-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.261 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 170 mg (0.784 mmol) of2-t-butoxycarbonyl-aminomethylmorpholine, 64 mg (42.2% of theory) of2-[2-ethoxy-5-(2-t-butoxycarbonylaminomethylmorpholine-4-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

Mass spectrum: 563 (M+H)

Example 142-[2-Ethoxy-5-(4-phenylpiperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.261 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 130 mg (0.784 mmol) of 1-phenylpiperazine, 38 mg (28.3% oftheory) of2-[2-ethoxy-5-(4-phenylpiperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.62, t, 3H, 2.72, s, 3H, 2.77, s, 3H, 3.25, m,8H, 4.38, q, 2H, 6.92, m, 2H, 7.02, d, 1H, 7.18-7.37, m, 3H, 7.94, dd,1H, 8.55, m, 1H, 9.79, bs, 1H.

Example 152-[2-Ethoxy-5-(3-hydroxy-3-methoxymethylpyrrolidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.261 mmol) of4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 100 mg (0.784 mmol) of3-hydroxy-3-methoxymethylpyrrolidine, 30 mg (23.5% of theory) of2-[2-ethoxy-5-(3-hydroxy-3-methoxymethylpyrrolidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

Mass spectrum: 478 (M+H)

Example 162-[2-Ethoxy-5-(4-methyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

1.23 g (3 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride are dissolved in 40 ml of dichloromethane and cooled to 0° C.After addition of a spatula tip of DMAP, 0.90 g (9.00 mmol) ofN-methylpiperazine are added, and the reaction mixture is stirred atroom temperature overnight. The mixture is diluted with dichloromethane,the organic phase is washed twice with water and dried over sodiumsulphate and the solvent is removed under reduced pressure.Crystallization from ether gives 1.25 g (88%) of a colourless solid.

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.59, t, 3H, 1.88, hex, 2H, 2.29,s, 3H, 2.51, m, 4H, 2.63, s, 3H, 3.00, t, 2H, 3.08, m, 4H, 4.33, quart.,2H, 7.17, d, 1H, 7.88, dd, 1H, 8.44, d, 1H, 9.75, s, 1H.

Example 172-[2-Ethoxy-5-(4-methyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-onelactate

100 mg (0.211 mmol) of2-[2-ethoxy-5-(4-methyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare suspended in 5 ml of ether and admixed with 20 mg of an 85% strengthsolution of lactic acid in water. The mixture is stirred at roomtemperature for 10 minutes and evaporated to dryness. The residue istitrated with ether and filtered off with suction. This gives 110 mg(92%) of2-[2-ethoxy-5-(4-methyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-onelactate.

200 MHz ¹H-NMR (DMSO-d₆): 0.92, t, 3H, 1.22, d, 3H, 1.31, t, 3H, 1.74,m, 1H, 2.15, s, 3H, 2.38, m, 4H, 2.81, t, 2H, 2.91, m, 4H, 4.05, quart.,1H, 4.21, quart., 2H, 7.40, d, 1H; 7.85, m, 2H, 11.71, s, broad, 1H.

Example 182-[2-Ethoxy-5-(4-methyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-onehydrochloride

100 mg (0.211 mmol) of2-[2-ethoxy-5-(4-methyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,-f][1,2,4]triazin-4-oneare suspended in 5 ml of diethyl ether, admixed with 0.23 ml of a 1Msolution of HCl in ether and stirred at room temperature for 15 minutes.The solvent is removed under reduced pressure. This gives 107 mg (97%)of2-[2-ethoxy-5-(4-methyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-onehydrochloride.

200 MHz ¹H-NMR (DMSO-d₆): 0.93, t, 3H, 1.35, t, 3H, 1.75, sex., 2H,2.72, s, 3H, 2.86, m, 4H, 3.15, m, 2H, 3.45, m, 2H, 3.81, m, 2H, 4.25,quart., 2H, 7.45, d, 1H, 7.95, m, 2H, 11.39, s, 1H, 11.90, s, 1H.

Example 192-[2-Ethoxy-5-(4-ethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

470 mg (1.14 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride are dissolved in 20 ml of dichloromethane and cooled to 0° C.390 mg (3.42 mmol) of N-ethylpiperazine are added, and the reactionmixture is stirred at room temperature overnight. The mixture is dilutedwith dichloromethane, the organic phase is washed twice with water anddried over sodium sulphate and the solvent is removed under reducedpressure. Crystallization from ether gives 370 mg (66%) of a colourlesssolid.

400 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.59, t, 3H, 1.88, hex, 2H, 2.42,quart., 2H, 2.56, m, 4H, 2.63, s, 3H, 3.00, t, 2H, 3.10, m, 4H; 4.33,quart., 2H, 7.17, d, 1H, 7.88, dd, 1H, 8.44, d, 1H, 9.75, s, 1H.

Example 202-[2-Ethoxy-5-(4-ethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-onehydrochloride

0.35 g (0.712 mmol) of2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare suspended in 8 ml of ether and dichloromethane is added until ahomogeneous solution is formed. 0.8 ml of a 1M solution of HCl in etheris added, and the mixture is stirred at room temperature for 20 minutesand filtered off with suction. This gives 372 mg (99%) of2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-onehydrochloride.

200 MHz ¹H-NMR (DMSO-d₆): 0.96, t, 3H, 1.22, t, 3H, 1.36, t, 3H, 1.82,sex., 2H, 2.61, s, 3H, 2.88, m, 2H, 3.08, m, 6H, 3.50, m, 2H, 3.70, m,2H, 4.25, quart., 2H, 7.48, d, 1H, 7.95, m, 2H, 11.42, s, 1H, 12.45, s,1H.

Example 212-[2-Ethoxy-5-(4-methyl-1-amino-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 0.04 g (0.097 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 0.03 g (0.29 mmol) of 1-amino-4-methylpiperazine, 40 mg(83%) of2-[2-ethoxy-5-(4-methyl-1-amino-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.09 (dichloromethane/methanol=19:1)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.59, t, 3H, 1.90, sex., 2H, 2.22,s, 3H, 2.40, m, 4H, 2.62, s, 3H, 2.71, m, 4H, 3.00, m, 2H, 4.32, quart.,2H, 7.14, d, 1H, 8.05, dd, 1H, 8.60, d, 1H.

Example 222-[2-Ethoxy-5-(4-hydroxyethyl-1-amino-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 0.04 g (0.097 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 0.04 g (0.29 mmol) of 1-amino-4-hydroxyethylpiperazine, 46mg (91%) of2-[2-ethoxy-5-(4-hydroxyethyl-1-amino-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.08 (dichloromethane/methanol=19:1)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.59, t, 3H, 1.90, sex., 2H, 2.49,m, 6H, 2.62, s, 3H, 2.71, m, 4H, 3.00, t, 2H, 3.55, t, 2H, 4.31, quart.,2H, 7.14, d, 1H, 8.05, dd, 1H, 8.60, d, 1H.

Example 232-[2-Ethoxy-5-(N,N-bishydroxyethyl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 0.04 g (0.097 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 0.04 g (0.29 mmol) of 1-amino-4-hydroxyethylpiperazine, 46mg (91%) of2-[2-ethoxy-5-(N,N-bishydroxyethyl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.08 (dichloromethane/methanol=19:1)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.53, t, 3H, 1.70, m, 2H, 1.86,sex., 2H, 2.9, m, 9H, 2.95, t, 2H, 3.09, t, 2H, 3.65, t, 4H, 4.28,quart., 2H, 7.14, d, 1H, 7.95, dd, 1H, 8.35, d, 1H.

Example 242-[2-Ethoxy-5-(4-dimethoxyphosphorylmethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 0.4 g (0.97 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride, 390 mg of triethylamine and 0.86 g (2.99 mmol) of4-dimethoxyphosphorylmethyl-piperazine trifluoroacetate, 321 mg (53%) of2-[2-ethoxy-5-(4-dimethoxyphosphoryl-methyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.4 (dichloromethane/methanol=20:1)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.60, t, 3H, 1.88, sex., 2H, 2.62,s, 3H, 2.75, m, 4H, 3.02, t, 2H, 3.11, m, 4H, 3.70, s, 3H, 3.75, s, 3H,4.35, quart., 2H, 5.30, s, 2H, 7.18, d, 1H, 7.88, dd, 1H, 8.45, d, 1H,9.71, s, 1H.

Example 252-[2-Ethoxy-5-(4-diethoxyphosphorylmethyl-piperidine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 0.4 g (0.97 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 0.86 g (3.7 mmol) of 4-diethoxyphosphorylmethyl-piperidine,366 mg (49%) of2-[2-ethoxy-5-(4-diethoxyphosphorylmethyl-piperidine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.4 (dichloromethane/methanol=20:1)

200 MHz ¹H-NMR (DMSO-d₆): 0.92, t, 3H, 1.20, t, 6H, 1.35, t, 3H, 1.75,m, 7H, 2.25, m, 2H, 2.82, t, 2H, 3.61, d, 2H, 3.95, quin., 4H, 4.21,quart., 2H, 7.38, d, 1H, 7.87, m, 2H, 11.70, s, 1H.

Example 262-[2-Ethoxy-5-(4-hydroxy-piperidine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 531 mg (1.29 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 393 mg (3.88 mmol) of 4-hydroxypiperidine, 400 mg (64%) of2-[2-ethoxy-5-(4-hydroxy-piperidine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

200 MHz ¹H-NMR (DMSO-d6): 0.941, t, 3H, 1.32, t, 3H, 1.45, m, 2H, 1.71,m, 4H, 2.48, s, 3H, 2.82, m, 4H, 3.11, m, 2H, 3.55, m, 1H; 4.20, quart.,2H, 4.72, d, 1H, 7.39, d, 1H, 7.87, m, 2H, 11.70, s, 1H.

Example 272-{2-Ethoxy-5-[4-(2-hydroxy-ethyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 411 mg (1 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 391 mg (3 mmol) of 4-hydroxyethylpiperazine, 380 mg (75%)of2-{2-ethoxy-5-[4-(2-hydroxy-ethyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.198 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.61, t, 3H, 1.87, hex., 3H, 2.60,m, 7H, 3.00, t, 2H, 3.10, m, 4H, 3.60, t, 2H, 4.36, quart., 2H, 7.18, d,1H, 7.89, dd, 1H, 8.47, d, 1H, 9.71, s, 1H.

Example 282-{2-Ethoxy-5-[4-(2-hydroxy-ethyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-onehydrochloride

200 mg (0.39 mmol) of2-{2-ethoxy-5-[4-(2-hydroxy-ethyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare suspended in ether, admixed with 2 ml of a 1M solution of HCl inether and stirred at room temperature for 20 minutes. The solvent isremoved, giving 209 mg (100%) of2-{2-ethoxy-5-[4-(2-hydroxy-ethyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-onehydrochloride.

200 MHz ¹H-NMR (DMSO-d6): 0.96, t, 3H, 1.35, t, 3H, 1.70, sex., 2H,2.59, s, 3H, 2.85, t, 2H, 2.99, t, 2H, 3.18, m, 4H, 3.59, d, 2H, 3.75,m, 4H, 4.25, quart., 2H, 7.49, d, 1H, 7.95, m, 2H, 10.62, s, 1H, 12.31,s, 1H.

Example 292-{2-Ethoxy-5-[4-(3-hydroxy-propyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 150 mg (0.37 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 158 mg (1.09 mmol) of 4-(3-hydroxypropyl)-piperazine, 167mg (83%) of2-{2-ethoxy-5-[4-(3-hydroxy-propyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.52 (dichloromethane/methanol=10:1)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.61, t, 3H, 1.70, m, 5; 2.62 m,8H, 3.00, t, 2H, 3.10, m, 4H, 3.72, t, 2H, 4.36, quart., 2H, 7.18, d,1H, 7.89, dd, 1H, 8.47, d, 1H, 9.71, s, 1H.

Example 30N-Allyl-4-ethoxy-N-(2-hydroxy-ethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulphonamide

By the same method, starting with 420 mg (1.02 mmol) (1 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 300 mg (3 mmol) of allylhydroxyethylamine, 400 mg (82%) ofN-allyl-4-ethoxy-N-(2-hydroxy-ethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulphonamideare obtained.

R_(f)=0.345 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.61, t, 3H, 1.90, m, 2H, 2.22, s,broad, 1H, 2.62, s, 3H, 2.99, t, 2H, 3.31, t, 2H, 3.78, t, 2H, 3.92, d,2H, 4.37, quart., 2H, 5.23, m, 2H, 5.71, m, 1H, 7.15, d, 1H, 7.98, dd,1H, 8.56, d, 1H, 9.66, s, 1H.

Example 31N-Ethyl-4-ethoxy-N-(2-hydroxy-ethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulphonamide

By the same method, starting with 411 mg (1.0 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 267 mg (3 mmol) of ethylhydroxyethylamine, 325 mg (70%) ofN-ethyl-4-ethoxy-N-(2-hydroxy-ethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulphonamideare obtained.

R_(f)=0.29 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.20, t, 3H, 1.61, t, 3H, 1.88,sex., 2H, 2.30, s, broad, 1H, 2.62, s, 3H, 2.99, t, 2H, 3.32, m, 4H,3.78, t, 2H, 3.80, m, 2H, 4.37, quart., 2H, 7.15, d, 1H, 7.98, dd, 1H,8.56, d, 1H, 9.70, s, 1H.

Example 32N,N-Diethyl-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulphonamide

By the same method, starting with 400 mg (0.97 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 210 mg (2.92 mmol) of diethylamine, 398 mg (89%) ofN,N-diethyl-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulphonamideare obtained.

R_(f)=0.49 (dichloromethane/methanol=20:1)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.20, t, 6H, 1.49, t, 1.61, t, 3H,1.88, sex., 2H, 2.30, s, broad, 1H, 2.62, s, 3H, 2.99, t, 2H, 3.32, m,4H, 3.78, t, 2H, 3.80, m, 2H, 4.37, quart., 2H, 7.15, d, 1H, 7.98, dd,1H, 8.56, d, 1H, 9.70, s, 1H.

Example 33N-(2-Methoxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulphonamide

By the same method, starting with 1.23 g (3 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 680 mg (9 mmol) of 2-methoxyethylamine, 900 mg (67%) ofN-(2-methoxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulphonamideare obtained.

R_(f)=0.25 (dichloromethane/methanol=95:5)

400 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.58, t, 3H, 1.88, sex., 2H, 2.62,s, 3H, 3.01, t, 2H, 3.18, quart., 2H, 3.30, s, 3H, 3.45, t, 2H, 4.32,quart., 2H, 5.12, t, 1H, 7.13, d, 1H, 7.97, dd, 1H, 8.53, d, 1H, 9.82,s, 1H.

Example 34N-(2-N,N-Dimethylethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulphonamide

By the same method, starting with 210 mg (0.49 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 130 mg (9 mmol) of 2-N,N-dimethylethylamine, 150 mg (59%)ofN-(2-N,N-dimethylethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulphonamideare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.62, m, 4H, 1.88, sex., 2H, 2.11,s, 6H, 2.39, t, 2H, 2.63, s, 3H, 3.01, m, 3H, 4.38, quart., 2H, 7.13, d,1H, 7.97, dd, 1H, 8.53, d, 1H; 9.82, s, 1H.

Example 35N-[3-(1-Morpholino)propyl]-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulphonamide

By the same method, starting with 1.23 g (3 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 1.3 g (9 mmol) of 3-(1-morpholino)-propylamine, 1.38 g(88%) ofN-[3-(1-morpholino)propyl]-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulphonamideare obtained.

R_(f)=0.23 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.58, t, 3H, 1.72, m, 2H, 1.88,sex., 2H, 2.46, m, 6H, 2.62, s, 3H, 3.01, t, 2H, 3.15, t, 2H, 3.71, t,4H, 4.32, quart., 2H, 7.13, d, 1H, 7.97, dd, 1H, 8.53, d, 1H, 9.79, s,1H.

Example 36N-{3-[1-(4-Methyl)piperazino]-propyl}-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulphonamide

By the same method, starting with 0.04 g (0.097 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 0.05 g (0.29 mmol) of3-[1-(4-methyl-)piperazino]-propylamine, 0.04 g (77%) ofN-{3-[1-(4-methyl)piperazino]-propyl}-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulphonamideis obtained.

R_(f)=0.11 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.55, t, 3H, 1.68, m, 2H, 1.88,sex., 2H, 2.27, s, 3H, 2.45, m, 8H, 2.62, s, 3H, 2.98, m, 3H, 3.10, t,2H, 3.46, s, 1H, 4.30, quart., 2H, 7.13, d, 1H, 7.97, dd, 1H, 8.53, d,1H.

Example 372-{2-Ethoxy-5-[4-(2-methoxy-ethyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 40 mg (0.097 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 40 mg (0.29 mmol) of 4-methoxyethylpiperazine, 50 mg (99%)of2-{2-ethoxy-5-[4-(2-methoxy-ethyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.27 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.61, t, 3H, 1.87, hex., 3H, 2.60,m, 9H, 2.97, t, 2H, 3.10, m, 4H, 3.60, s, 3H, 3.46, t, 2H, 4.36, quart.,2H, 7.18, d, 1H, 7.89, dd, 1H, 8.47, d, 1H, 9.71, s, 1H.

Example 382-{2-Ethoxy-5-[4-(2-N,N-dimethyl-ethyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 40 mg (0.097 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 50 mg (0.29 mmol) of 4-(2-N,N-dimethyl)-ethylpiperazine, 50mg (99%) of2-{2-ethoxy-5-[4-(2-N,N-dimethyl-ethyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.11 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.61, t, 3H, 1.87, hex., 3H, 2.20,s, 6H, 2.42, m, 4H, 2.58, m, 4H, 2.63, s, 3H, 2.99, m, 3H, 3.10, m, 4H,4.36, quart., 2H, 7.18, d, 1H, 7.89, dd, 1H, 8.47, d, 1H, 9.71, s, 1H.

Example 392-{2-Ethoxy-5-[4-(3-N,N-dimethyl-propyl)-piperazin-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.243 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 130 mg (0.73 mmol) of 4-(3-N,N-dimethyl)-propylpiperazine,72 mg (54%) of2-{2-ethoxy-5-[4-(3-N,N-dimethyl-propyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.08 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.61, t, 3H, 1.87, sex., 3H, 2.20,s, 6H, 2.25, m, 2H, 2.38, t, 2H, 2.52, m, 4H, 2.63, s, 3H, 2.99, m, 6H,4.33, quart., 2H, 7.18, d, 1H, 7.89, dd, 1H, 8.47, d, 1H, 9.71, s, 11H.

Example 402-[2-Ethoxy-5-(4-dioxolano-piperidine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 100 mg (0.243 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 100 mg (0.73 mmol) of 4-dioxolanopiperidine, 111 mg (88%)of2-[2-ethoxy-5-(4-dioxolano-piperidine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.61, t, 3H, 1.80, m, 6H, 2.63, s,3H, 2.99, t, 2H, 3.20, m, 4H, 3.90, s, 4H, 4.33, quart., 2H, 7.18, d,1H, 7.89, dd, 1H, 8.47, d, 1H, 9.71, s, 1H.

Example 412-[2-Ethoxy-5-(4-(5-methyl-4-furoxanecarbonyl)-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

410 mg (1.0 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride are dissolved in 10 ml of dichloromethane and cooled to 0° C.590 mg (2.00 mmol) of 1-(5-methyl-4-furoxanecarbonyl)-piperazinetrifluoroacetate and 400 mg of triethylamine are added, and the reactionmixture is stirred at room temperature overnight. The mixture is dilutedwith dichloromethane, the organic phase is washed with ammonium chloridesolution, 1M hydrochloric acid and water and dried over sodium sulphateand the solvent is removed under reduced pressure. Crystallization fromether gives 448 mg (74%) of a colourless solid.

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.59, t, 3H, 1.88, hex, 2H, 2.25,s, 3H, 2.63, s, 3H, 3.00, t, 2H, 3.20, m, 4H, 3.90, m, 2H, 4.02, m, 2H,4.33, quart., 2H, 7.19, d, 1H, 7.89, dd, 1H, 8.48, d, 1H, 9.57, s, 1H.

Example 422-{2-Ethoxy-5-[4-acetyl-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 40 mg (0.097 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 40 mg (0.29 mmol) of N-acetylpiperazine, 9 mg (18%) of2-{2-ethoxy-5-[4-acetyl-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.34 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.61, t, 3H, 1.87, sex., 3H, 2.05,s, 3H, 2.63, s, 3H, 3.00, m, 6H, 3.59, m, 2H, 3.72, m, 2H, 4.33, quart.,2H, 7.18, d, 1H, 7.89, dd, 1H, 8.47, d, 1H, 9.71, s, 1H.

Example 432-{2-Ethoxy-5-[4-formyl-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 40 mg (0.097 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 30 mg (0.29 mmol) of N-formylpiperazine, 35 mg (73%) of2-{2-ethoxy-5-[4-formyl-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.29 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.61, t, 3H, 1.87, sex., 3H, 2.05,s, 3H, 2.63, s, 3H, 3.00, m, 6H, 3.50, m, 2H, 3.69, m, 2H, 4.33, quart.,2H, 7.18, d, 1H, 7.89, dd, 1H, 8.00, s, 1H, 8.47, d, 1H, 9.71, s, 1H.

Example 442-[2-Ethoxy-5-(3-butylsydnoneimine)-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

110 mg (0.6 mmol) of 3-butylsydnoneimine hydrochloride are dissolved in2.5 ml of pyridine and cooled to 0° C. 210 mg (0.5 mmol) of4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride are added, and the reaction mixture is stirred for 2 hours at0° C. and overnight at room temperature. The mixture is diluted withdichloromethane, the organic phase is washed with water and dried oversodium sulphate and the solvent is removed under reduced pressure.Chromatography (dichloromethane/methanol) gives 16 mg (6%) of2-[2-ethoxy-5-(3-butylsydnoneimine)-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one.

R_(f)=0.41 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.01, 2t, 6H, 1.47, sex., 2H, 1.55, t, 3H, 1.88,m, 2H, 2.04, quin., 2H, 2.62, s, 3H, 2.98, t, 2H, 4.29, quart., 2H,4.41, t, 2H, 7.08, d, 1H, 7.56, s, 1H, 7.98, dd, 1H, 8.58, d, 1H; 9.79,s, broad, 1H.

Example 455-Methyl-2-[5-(4-methyl-piperazine-1-sulphonyl)-2-propoxy-phenyl]-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

0.85 g (2 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl)-benzenesulphonylchloride are dissolved in 20 ml of dichloromethane and cooled to 0° C.After addition of a spatula tip of DMAP, 0.60 g (6.00 mmol) ofN-methylpiperazine is added and the reaction mixture is stirred at roomtemperature overnight. The mixture is diluted with dichloromethane, theorganic phase is washed with ammonium chloride solution and dried oversodium sulphate and the solvent is removed under reduced pressure.Crystallization from ether gives 0.80 g (77%) of a colourless solid.

R_(f)=0.233 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.00, t, 3H, 1.15, t, 3H, 1.87, hex, 2H, 1.99,hex., 2H, 2.30, s, 3H, 2.52, m, 4H, 2.62, s, 3H, 2.99, t, 2H, 3.10, m,4H, 4.21, t, 2H, 7.17, d, 1H, 7.87, dd, 1 h, 8.48, d, 1H, 9.70, s, 1H.

Example 465-Methyl-2-[5-(4-methyl-piperazine-1-sulphonyl)-2-propoxy-phenyl]-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-onehydrochloride

22 mg (0.045 mmol) of5-methyl-2-[5-(4-methyl-piperazine-1-sulphonyl)-2-propoxy-phenyl]-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare dissolved in 2 ml of ether and 1 ml of dichloromethane and admixedwith 0.1 ml of a 1M solution of HCl in ether. After 20 minutes, theprecipitate is filtered off with suction and dried.

200 MHz ¹H-NMR (CDCl₃): 0.95, t, 3H, 1.75, m, 2H, 2.56, s, 3H, 2.75, m,4H, 2.97, t, 2H, 3.15, m, 2H, 3.44, m, 2H, 3.81, m, 2H, 4.15, t, 2H,7.47, d, 1H, 7.95, m, 2H, 11.12, s, 1H, 12.22, s, 1H.

Example 472-[5-(4-Hydroxypiperidine-1-sulphonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 850 mg (2 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 610 mg (6 mmol) of 4-hydroxypiperidine, 736 mg (75%) of2-[5-(4-hydroxypiperidine-1-sulphonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.07 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.16, t, 3H, 1.80, m, 9H, 2.65, s,3H, 3.00, m, 4H, 3.32, m, 2H, 3.85 μm, 1H, 4.22, t., 2H, 7.17, d, 1H;7.89, dd, 1H, 8.50, d, 1H, 11.70, s, 1H.

Example 482-[5-(4-Hydroxymethylpiperidine-1-sulphonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 35 mg (0.3 mmol) of 4-hydroxymethylpiperidine, 41 mg (82%)of2-[5-(4-hydroxymethylpiperidine-1-sulphonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.52 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 1.001, t, 3H, 1.16, t, 3H, 1.60, m, 4H, 1.82, m,5H, 2.31, t, 2H, 2.62, s, 3H, 2.98, t, 2H; 3.48, d, 2H, 3.85, d, 2H,4.21, t, 2H; 7.17, d, 1H, 7.88, dd, 1H, 8.45, d, 1H; 9.71, s, 1H.

Example 492-{5-[4-(2-hydroxyethyl)-piperazine-1-sulphonyl]-2-propoxy-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 39 mg (0.3 mmol) of 4-hydroxymethylpiperazine, 50 mg (96%)of2-{5-[4-(2-hydroxyethyl)-piperazine-1-sulphonyl]-2-propoxy-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.43 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.15, t, 3H, 1.88, m, 2H, 2.00, m,2H, 2.62, m, 9H, 3.00, t, 2H, 3.07, m, 4H, 3.58, t, 2H, 4.23, t, 2H,7.19, d, 1H, 7.88, dd, 1H, 8.43, d, 1H, 9.85, s, 1H.

Example 50N-(1,1-Dioxotetrahydro-1)-6-thiophene-3-yl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo-[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 41 mg (0.3 mmol) of 2-aminosulpholane, 8 mg (14%) ofN-(1,1-dioxotetrahydro-1λ⁶-thiophene-3-yl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo-[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamideare obtained.

R_(f)=0.49 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.15, t, 3H, 1.85, m, 2H, 1.99, m,2H, 2.30, m, 1H, 2.50, m, 1H, 2.62, s, 3H, 2.95, m, 4H, 3.21, m, 1H,4.20, m, 3H, 5.98, s, 1H, 7.18, d, 1H, 7.98, dd, 1H, 8.51, d, 1H, 9.71,s, 1H.

Example 51N-(2-Dimethylaminoethyl)-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 31 mg (0.3 mmol) of 1,1,4-trimethyldiaminoethane, 39 mg(79%) ofN-(2-dimethylaminoethyl)-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamideare obtained.

R_(f)=0.28 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.15, t, 3H, 1.88, m, 2H, 2.01, m,2H, 2.25, s, 6H, 2.50, t, 2H, 2.62, s, 3H, 2.82, s, 3H, 3.01, t, 2H,3.18, t, 2H, 4.21, t, 2H, 7.16, d, 1H, 7.91, dd, 1H, 8.50, d, 1H, 9.70,s, 1H.

Example 523-(5-Methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-N-(3-morpholin-4-yl-propyl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 43 mg (0.3 mmol) of 1-(3-aminopropyl)-morpholine, 52 mg(97%) of3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-N-(3-morpholin-4-yl-propyl)-4-propoxy-benzenesulphonamideare obtained.

R_(f)=0.33 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.15, t, 3H, 1.71, m, 2H, 1.93, m,4H, 2.43, m, 6H, 2.62, s, 3H, 2.98, t, 2H, 3.12, t, 2H, 3.70, m, 4H,4.21, t, 2H, 7.15, d, 1H, 7.96, dd, 1H, 8.55, d, 1H, 9.85, s, 1H.

Example 53N,N-Bis-(2-hydroxyethyl)-3-(S-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 32 mg (0.3 mmol) of bishydroxyethylamine, 34 mg (69%) ofN,N-bis-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamideare obtained.

R_(f)=0.36 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.15, t, 3H, 1.85, m, 2H, 1.97, m,2H, 2.60, s, 3H, 2.98, t, 2H, 3.33, t, 4H, 3.87, t, 4H, 4.20, t, 2H,7.15, d, 1H, 7.92, dd, 1H, 8.49, d, 1H; 9.85, s, 1H.

Example 54N-(3-Hydroxybenzyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 37 mg (0.3 mmol) of 3-hydroxybenzylamine, 4 mg (8%) ofN-(3-hydroxybenzyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamideare obtained.

R_(f)=0.43 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.13, t, 3H, 1.83, m, 2H, 1.96, m,2H, 2.59, s, 3H, 2.96, t, 2H, 4.16, m, 4H, 5.05, t, 1H, 6.52, s, 1H,6.70, m, 2H, 7.06, m, 2H, 7.93, dd, 1H, 8.41, d, 1H, 9.77, s, 1H.

Example 55N-Ethyl-N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 27 mg (0.3 mmol) of ethylhydroxyethylamine, 18 mg (38%) ofN-ethyl-N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamideare obtained.

R_(f)=0.48 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.15, 2t, 6H, 1.75, s, 2H, 1.85, m,2H, 1.98, m, 2H, 2.40, s, 1H, 2.62, s, 3H, 2.99, t, 2H, 3.32, m, 4H,3.90, quart., 2H, 4.21, quart., 2H, 7.15, d, 1H; 7.95, dd, 1H; 8.55, d,1H, 9.73, s, 1H.

Example 56N-(3-Ethoxypropyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 31 mg (0.3 mmol) of 3-ethoxypropylamine, 47 mg (96%) ofN-(3-ethoxypropyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamideare obtained.

R_(f)=0.60 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.15, m, 6H, 1.89, m, 7H, 2.62, s,3H, 3.00, t, 2H, 3.12, quart., 2H, 3.46, m, 4H, 4.20, t, 2H, 5.52, m,1H, 7.15, d, 1H, 7.98, dd, 1H, 8.55, d, 1H, 9.85, s, 1H.

Example 57 2-[5(4-Hydroxypiperidine-1-sulphonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 212 mg (0.5 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 152 mg (1.5 mmol) of 4-hydroxypiperidine, 125 mg (50%) of2-[5(4-hydroxypiperidine-1-sulphonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-j][1,2,4]triazin-4-oneare obtained.

R_(f)=0.07 (dichloromethane/methanol=19:1)

200 MHz ¹H-NMR (CDCl₃): 1.05, t, 3H, 1.18, t, 3H, 1.98, m, 8H, 2.71, s,3H, 3.10, m, 2H, 3.28, m, 4H, 3.88, m, 1H, 4.28, t, 2H, 7.21, d, 1H,7.97, dd, 1H, 8.45, d, 1H. 10.45, s, 1H.

Example 583-(5-Methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-N-pyridin-4-yl-benzenesulphonamide

By the same method, starting with 85 mg (0.2 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 56 mg (0.6 mmol) of 4-aminopyridine, 24 mg (25%) of3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-N-pyridin-4-yl-benzenesulphonamideare obtained after 18 hours at reflux in 1 ml of THF.

R_(f)=0.13 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃+CD₃OD): 1.01, t, 3H, 1.09, t, 3H, 1.90, m, 4H,2.60, s, 3H, 2.99, t, 2H, 4.16, t, 2H, 7.05, d, 2H, 7.15, d, 1H, 7.88,d, 2H, 8.05, dd, 1H, 8.41, d, 1H.

Example 59N,N-Diethyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 22 mg (0.6 mmol) of diethylamine, 42 mg (92%) ofN,N-diethyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamideare obtained.

R_(f)=0.64 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.18, 2t, 9H, 1.92, 2 hex., 4H,2.62, s, 3H, 3.00, t, 2H, 3.29, quart., 4H, 4.21, t, 2H, 7.13, d, 1H,7.93, dd, 1H, 8.51, d, 1H, 9.85, s, 1H.

Example 601-[3-(5-Methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonyl]-piperidine-4-carboxylicacid

By the same method, starting from 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 14 mg (0.6 mmol) of piperidinecarboxylic acid in 1 ml of amixture of THF and water (1:1) with 26.5 mg of sodium carbonate, 21 mg(41%) of1-[3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonyl]-piperidine-4-carboxylicacid are obtained.

R_(f)=0.28 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 0.90, t, 3H, 1.04, t, 3H, 1.80, m, 4H, 2.21, m,2H, 2.51, s, 3H, 2.85, m, 2H, 3.56, m, 6H, 4.10, t, 2H, 7.12, d, 1H,7.71, dd, 1H, 8.10, d, 1H, 10.72, s, broad, 1H.

Example 615-Methyl-2-[5-(morpholine-4-sulphonyl)-2-propoxy-phenyl]-7-propyl-3H-imidazo[5,1-j][1,2,4]triazin-4-one

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 26 mg (0.3 mmol) of morpholine, 34 mg (71%) of5-methyl-2-[5-(morpholine-4-sulphonyl)-2-propoxy-phenyl]-7-propyl-3H-imidazo[5,1f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.64 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.16, t, 3H, 1.89, hex., 2H, 2.00,hex., 2H, 2.63, s, 3H, 3.02, m, 4H, 4.25, t, 2H, 7.19, d, 1H, 7.89, dd,1H, 8.48, d, 1H, 9.78, s, 1H.

Example 62N-(2-Hydroxyethyl)-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 23 mg (0.63 mmol) of methylhydroxyethylamine, 25 mg (54%)ofN-(2-hydroxyethyl)-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamideare obtained.

R_(f)=0.53 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.15, t, 3H, 1.82, m, 2H, 1.99,hex., 2H, 2.40, s, broad, 1H, 2.62, s, 3H, 2.89, s, 3H, 2.99, t, 2H,3.21, t, 2H, 3.80, s, broad, 2H, 4.21, t, 2H, 7.16, d, 1H, 7.92, dd, 1H,8.50, d, 1H, 9.79, s, 1H.

Example 63N-(2-Hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-N-propyl-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 31 mg (0.6 mmol) of propylhydroxyethylamine, 20 mg (40%) ofN-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl)-4-propoxy-N-propyl-benzenesulphonamideare obtained.

R_(f)=0.52 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 0.90, t, 3H, 1.01, t, 3H, 1.15, t, 3H, 1.52, m,2H, 1.88, m, 2H, 2.00, m, 2H, 2.40, s, 1H, 2.63, s, 3H, 3.01, t, 2H,3.22, m, 4H, 3.80, quart., 2H, 4.21, t, 2H, 7.15, d, 2H, 7.95, dd, 1H,8.55, d, 1H, 9.75, s, 1H.

Example 64N-[2-(3,4-Dimethoxy-phenyl)ethyl]-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 59 mg (0.3 mmol) of N-methyl-3,4-dimethoxyphenylethylamine,45 mg (78%) ofN-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamideare obtained.

R_(f)=0.35 (dichloromethane/methanol=19:1)

200 MHz ¹H-NMR (CDCl₃): 0.90, t, 3H, 1.07, t, 3H, 1.78, m, 2H, 1.92, m,2H, 2.55, s, 3H, 2.73, s, 3H, 2.78, m, 2H, 2.89, t, 2H, 3.23, t, 2H,3.80, s, 6H, 4.15, t, 2H, 6.65, m, 3H, 7.05, d, 1H, 7.75, dd, 1H, 8.41,d, 1H, 9.67, s, 1H.

Example 65N-Allyl-N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 31 mg (0.3 mmol) of allylhydroxyethylamine, 34 mg (70%) ofN-allyl-N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamideare obtained.

R_(f)=0.52 (dichloromethane/methanol=9:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.15, t, 3H, 1.85, m, 2H, 1.99, m,2H, 2.38, s, broad, 1H, 2.63, s, 3H, 3.00, t, 2H, 3.32, t, 2H, 3.86, t,2H, 3.90, d, 2H, 4.25, t, 2H, 5.21, m, 2H, 5.71, m, 1H, 7.15, d, 1 h,7.95, dd, 1H, 8.55, d, 1H, 9.77, s, 1H.

Example 66N-Allyl-N-cyclopentyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 38 mg (0.3 mmol) of allylcyclopentylamine, 33 mg (64%) ofN-allyl-N-cyclopentyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamideare obtained.

R_(f)=0.43 (dichloromethane/methanol=19:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.15, t, 3H, 1.53, m, 9H, 2.00, m,4H, 2.63, s, 3H, 3.00, t, 2H, 3.80, m, 2H, 4.21, t, 2H, 5.20, m, 2H,5.88, m, 1H, 7.12, d, 1H, 7.95, dd, 1H, 8.55, d, 1H, 9.75, s, 1H.

Example 67N-Allyl-N-ethyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl)-4-propoxybenzenesulphonamide

By the same method, starting with 42 mg (0.1 mmol) of4-propoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 26 mg (0.3 mmol) of allylethylamine, 30 mg (64%) ofN-allyl-N-ethyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonamideare obtained.

R_(f)=0.44 (dichloromethane/methanol=19:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.15, t, 6H, 1.89, m, 2H, 2.01, m,2H, 2.63, s, 3H, 3.00, t, 2H, 3.27, quart., 2H, 3.87, d, 2H, 4.23, t,2H, 5.20, m, 2H, 5.72, m, 1H, 7.15, d, 1H, 7.95, dd, 1H, 8.55, d, 1H,9.80, s, 1H.

Example 682-[2-Ethoxy-4-methoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

20 mg (0.045 mmol) of4-ethoxy-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride are dissolved in 0.5 ml of dichloromethane and admixed with aspatula tip of dimethylaminopyridine and 14 mg (0.136 mmol) ofN-methylpiperazine, and the reaction mixture is stirred at roomtemperature overnight. Purification over silica gel gives 12.8 mg (55%)of2-[2-ethoxy-4-methoxy-5-(4-methylpiperazine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one.

R_(f)=0.22 (dichloromethane/methanol=20:1).

200 MHz ¹H-NMR (CDCl₃): 0.94, t, 3H, 1.55, t, 3H, 1.80, m, 2H, 2.24, s,3H, 2.42, t, 4H, 2.55, s, 3H, 2.92, t, 2H, 3.19, t, 4H, 3.91, s, 3H,4.25, quart., 2H, 6.48, s, 1H, 8.57, s, 1H, 9.54, s, 1H.

Example 692-{2-Ethoxy-5-[4-(2-hydroxyethyl)-piperazine-1-sulphonyl]-4-methoxy-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 20 mg (0.045 mmol) of4-ethoxy-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 18 mg (0.14 mmol) of 4-hydroxyethylpiperazine, 11 mg (46%)of2-{2-ethoxy-5-[4-(2-hydroxyethyl)-piperazine-1-sulphonyl]-4-methoxyphenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.34 (dichloromethane/methanol=15:1)

200 MHz ¹H-NMR (CDCl₃): 0.94, t, 3H, 1.55, t, 3H, 1.80, m, 3H, 2.52, m,9H, 2.92, t, 2H, 3.20, t, 4H, 3.44, t, 2H, 3.92, s, 3H, 4.25, quart.,2H, 6.49, s, 1H, 8.56, s, 1H, 9.55, s, 1H.

Example 704-Ethoxy-N-ethyl-N-(2-hydroxyethyl)-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonamide

By the same method, starting from 20 mg (0.045 mmol) of4-ethoxy-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 12 mg (0.14 mmol) of ethylhydroxyethylamine, 8 mg (34%) of4-ethoxy-N-ethyl-N-(2-hydroxyethyl)-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonamideare obtained.

R_(f)=0.45 (dichloromethane/methanol=15:1)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.18, t, 3H, 1.61, t, 2H, 1.88, m,2H, 2.39, s, broad, 1H, 2.65, s, 3H, 3.00, t, 2H, 3.38, quart., 2H,3.45, t, 2H, 3.78, m, 2H, 4.01, s, 3H, 4.20, quart., 2H, 6.58, s, 1H,8.67, s, 1H, 9.61, s, 1H.

Example 714-Ethoxy-N-(4-ethoxyphenyl)-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonamide

By the same method, starting with 20 mg (0.045 mmol) of4-ethoxy-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzene-sulphonylchloride and 19 mg (0.14 mmol) of 4-ethoxyaniline, 7 mg (34%) of4-ethoxy-N-(4-ethoxyphenyl)-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonamideare obtained.

R_(f) 0.36 (dichloromethane/methanol=20:1)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.33, t, 3H, 1.59, t, 3H, 1.86,hex., 2H, 2.62, s, 3H, 3.02, t, 2H, 3.92, quart., 2H, 4.11, s, 3H, 4.31,quart., 2H, 6.58, s, 1H, 6.72, d, 2H, 6.88, s, broad, 1H, 6.99, d, 2H,8.50, s, 1H, 9.59, s, 1H.

Example 724-Ethoxy-N-ethyl-N-(2-hydroxy-ethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulphonamide

0.64 g (1.5 mmol) of4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride are dissolved in 20 ml of dichloromethane and cooled to 0° C.After addition of a spatula tip of dimethylaminopyridine, 0.40 g (4.50mmol) of 2-(ethylamino)-ethanol are added, and the reaction mixture isstirred at room temperature overnight. The mixture is diluted withdichloromethane, the organic phase is washed with water and dried oversodium sulphate and the solvent is removed under reduced pressure.Chromatography (dichloromethane/methanol=95:5) gives 0.454 g (63%) of acolourless solid.

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.20, t, 3H, 1.35, t, 3H, 1.61, t,3H, 1.88, sex., 2H, 2.25, s, broad, 1H; 3.01, m, 4H, 3.32, m, 4H, 3.70,m, 2H, 3.80, m, 2H, 4.37, quart., 2H, 7.15, d, 1H; 7.98, dd, 1H; 8.56,d, 1H, 9.70, s, 1H.

Example 73N-(2-Methoxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulphonamide

By the same method, starting with 40 mg (0.094 mmol) of4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 21 mg (0.282 mmol) of 2-methoxyethylamine, 15 mg (34%) ofN-(2-methoxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulphonamideare obtained.

R_(f)=0.2 (ethyl acetate/cyclohexane=2:1)

200 MHz ¹H-NMR (CDCl₃): 0.97, t, 3H, 1.25, t, 3H, 1.53, t, 3H, 1.82,sex., 2H, 2.97, m, 4H, 3.11, m, 2H, 3.22, s, 3H, 3.39, t, 2H, 4.37,quart., 2H, 5.00, t, 1H, 7.17, d, 1H, 7.97, dd, 1H, 8.53, d, 1H, 9.82,s, 1H.

Example 74N,N-Bis-(2-methoxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulphonamide

By the same method, starting with 40 mg (0.094 mmol) of4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 38 mg (0.28 mmol) of bismethoxyethylamine, 17 mg (34%) ofN,N-bis-(2-methoxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulphonamideare obtained.

R_(f)=0.34 (ethyl acetate/cyclohexane=2:1)

200 MHz ¹H-NMR (CDCl₃): 0.97, t, 3H, 1.27, t, 3H, 1.53, t, 3H, 1.80,sex., 2H, 2.95, m, 4H, 3.22, s, 6H, 3.39, m, 4H, 3.49, m, 4H, 4.27,quart., 2H, 7.17, d, 1H, 7.97, dd, 1H, 8.53, d, 1H; 9.82, s, 1H.

Example 752-[5-(4-Hydroxypiperidine-1-sulphonyl)-2-ethoxyphenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one

By the same method, starting with 640 mg (1.5 mmol) of4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 460 mg (4.5 mmol) of 4-hydroxypiperidine, 485 mg (66%) of2-[5-(4-hydroxy-piperidine-1-sulphonyl)-2-ethoxyphenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-j][1,2,4]triazin-4-oneare obtained.

R_(f)=0.37 (dichloromethane/methanol=19:1)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.32, t, 3H, 1.60, t, 3H, 1.80, m,7H, 2.97, m, 6H, 3.30, m, 2H, 3.82, m, 1H, 4.34, quart., 2H, 7.17, d,1H, 7.90, dd, 1H, 8.45, d, 1H. 9.75, s, 1H.

Example 762-[5-(4-Hydroxymethylpiperidine-1-sulphonyl)-2-ethoxy-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 40 mg (0.094 mmol) of4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 33 mg (0.28 mmol) of 4-hydroxymethylpiperidine, 23 mg (48%)of2-[5-(4-hydroxymethylpiperidine-1-sulphonyl)-2-ethoxyphenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.38 (dichloromethane/methanol=10:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.33, t, 3H, 1.60, t, 3H, 1.80, m,8H, 2.41, m, 2H, 3.00, m, 4H, 3.56, m, 4H, 4.35, quart, 2H; 7.17, d, 1H,7.88, dd, 1H, 8.45, d, 1H, 9.71, s, 1H.

Example 772-{2-Ethoxy-5-[4-(2-hydroxyethyl)-piperazine-1-sulphonyl]-phenyl}-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

By the same method, starting with 40 mg (0.094 mmol) of4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 37 mg (0.28 mmol) of 4-hydroxyethylpiperazine, 35 mg (71%)of2-{2-ethoxy-5-[4-(2-hydroxyethyl)-piperazine-1-sulphonyl]-phenyl}-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.65 (dichloromethane/methanol=10:1)

Example 782-[2-Ethoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one

By the same method, starting with 640 mg (1.50 mmol) of4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 450 mg (4.5 mmol) of 4-hydroxyethylpiperazine, 495 mg (66%)of2-[2-ethoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare obtained.

R_(f)=0.30 (dichloromethane/methanol=19:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.35, t, 3H, 1.61, t, 3H, 1.89,sex., 2H, 2.31, s, 3H, 2.53, m, 4H, 3.05, m, 8H, 4.35, quart., 2H, 7.17,d, 1H, 7.89, dd, 1H, 8.48, d, 1H, 9.65, s, 1H.

Example 792-[2-Ethoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-onehydrochloride

300 mg (0.61 mmol) of2-[2-ethoxy-5-(4-methyl-piperazine-1-sulphonyl)-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneare dissolved in a mixture of ether and dichloromethane and admixed with2 ml of a 1M solution of HCl in ether. After 20 minutes, theprecipitated solid is filtered off with suction and dried.

200 MHz ¹H-NMR (DMSO-d₆): 0.95, t, 3H, 1.32, 2t, 6H, 1.80, sex., 2H,2.76, m, 4H, 3.01, m, 4H, 3.15, m, 2H, 3.44, m, 2H, 3.81, m, 2H, 4.25,quart., 2H, 7.49, d, 1H, 7.95, m, 2H, 11.25, s, 1H, 12.30, s, 1H.

Example 803-(5-Ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-N-(3-morpholin-4-yl-propyl)-4-ethoxybenzenesulphonamide

By the same method, starting with 640 mg (1.5 mmol) of4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 650 mg (4.5 mmol) of 1-(3-aminopropyl)-morpholine, 476 mg(59%) of3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-N-(3-morpholin-4-yl-propyl)-4-ethoxy-benzenesulphonamideare obtained.

R_(f)=0.18 (dichloromethane/methanol=19:1)

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H, 1.32, t, 3H, 1.60, t, 3H, 1.70, m,3H, 1.89, sex., 2H, 2.43, m, 7H, 3.01, m, 4H, 3.15, t, 2H, 3.70, m, 4H,4.35, quart., 2H, 7.15, d, 1H, 7.95, dd, 1H, 8.55, d, 1H; 9.82, s, 1H.

Example 81N-(2-Hydroxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-N-propyl-benzenesulphonamide

By the same method, starting with 640 mg (1.5 mmol) of4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and 464 mg (4.5 mmol) of propylhydroxyethylamine, 600 mg (81%)ofN-(2-hydroxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-N-propylbenzenesulphonamideare obtained.

R_(f)=0.73 (dichloromethane/methanol=10:1)

200 MHz ¹H-NMR (CDCl₃): 0.91, t, 3H, 1.01, t, 3H, 1.32, t, 3H, 1.62, m,5H, 1.88, m, 2H, 2.32, s, 1H, 3.01, m, 4H, 3.22, m, 4H, 3.80, m, 2H,4.35, t, 2H, 7.15, d, 2H, 7.95, dd, 1H, 8.55, d, 1H, 9.75, s, 1H.

The sulphonamides listed in Tables 1, 2, 3, 4 and 6 below were preparedby means of automated parallelsynthesis from4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonylchloride and the appropriate amine using one of the three standardprocedures below.

The sulphonamides listed in Table 5 were prepared by the same methods bymeans of automated parallelsynthesis from4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-δ][1,2,4]triazin-2-yl)-benzenesulphonylchloride and the appropriate amine.

The purity of the final products was determined by means of HPLC, andthey were characterized by LC-MS. The content of the desired compoundaccording to HPLC-MS is given in percent in the tables in the column“HPLC”. Standard procedure A was used with amines having acidicfunctionalities, standard procedure B was used with amines havingneutral functionalities, standard procedure C was used with amineshaving additional basic functionalities.

In the structural formulae of Tables 1, 2, 3, 4, 5 and 6 below, hydrogenatoms are in some cases not shown. Nitrogen atoms having a free valencyare therefore to be understood as —NH— radical.

Standard Procedure A: Reaction of Amines Having Acidic Functionalities

0.05 mmol of amine, 0.042 mmol of sulphonyl chloride and 0.10 mmol ofNa₂CO₃ are initially charged, and 0.5 ml of a mixture of THF/H₂O ispipetted in by hand. After 24 h at RT, the mixture is admixed with 0.5ml of 1M H₂SO₄ solution and filtered through a two-phase cartridge (500mg of Extrelut (upper phase) and 500 mg of SiO₂, mobile phase ethylacetate). The product is obtained after concentrating the filtrate underreduced pressure.

Standard Procedure B: Reaction of Amines Having Neutral Functionalities

0.125 mmol of amine are initially charged and 0.03 mmol of sulphonylchloride as a solution in 1,2-dichloroethane is pipetted in by thesynthesizer. After 24 h, the mixture is admixed with 0.5 ml of 1M H₂SO₄and filtered through a two-phase cartridge (500 mg of Extrelut (upperphase) and 500 mg of SiO₂, mobile phase: ethyl acetate). The filtrate isconcentrated under reduced pressure.

Standard Procedure C: Reaction of Amines Having Basic Functionalities

0.05 mmol of amine are initially charged and 0.038 mmol of sulphonylchloride as a solution in 1,2-dichloroethane and 0.05 mmol oftriethylamine as a solution in 1,2-dichloroethane is pipetted in by thesynthesizer. After 24 h, the solution is initially admixed with 3 ml ofsaturated NaHCO₃ solution and the reaction mixture is filtered through atwo-phase cartridge. The product is obtained after concentrating thefiltrate under reduced pressure.

All reactions are monitored by thin-layer chromatography. If thereaction is not complete after 24 h at RT, the mixture is heated to 60°C. for a further 12 h and the experiment is subsequently terminated.

TABLE 1 Ex. MW MZ + No. Structure [g/mol] HPLC H 82

525.6315 83 526 83

525.6315 71 526 84

555.658 91 556 85

477.5869 76 478 86

525.6315 81 526 87

463.5598 65 464 88

531.6793 83 532 89

463.5598 40 464 90

463.5598 44 464 91

581.6962 76 582 92

475.5273 61 476 93

421.4785 80 422 94

475.5709 81 476 95

491.614 97 492 96

567.7127 80 568 97

521.6405 94 522 98

477.5869 70 478 99

535.6239 88 536 100

553.6857 88 554 101

529.6197 85 530 102

539.6586 91 540 103

520.6121 55 521 104

502.6404 82 503 105

564.7121 86 565 106

524.6467 85 525 107

538.6738 85 539 108

546.694 84 547 109

504.6127 90 505

TABLE 2 Ex. MW MZ + No. Structure [g/mol] HPLC H 110

507.6134 74 508 111

539.6586 75 540 112

599.7115 83 600 113

535.6675 60 536 114

521.6405 95 522 115

569.6851 84 570 116

608.5486 85 608 117

569.6851 88 570 118

463.5598 94 464 119

535.6675 93 536 120

517.6522 71 518 121

561.7058 92 562 122

539.6586 85 540 123

518.6834 87 519 124

588.1307 30 588 125

550.685 83 551 126

542.7057 77 543 127

502.6404 91 503 128

490.6292 45 491 129

568.7003 66 569 130

534.6828 86 535 131

580.7551 95 581 132

576.7205 87 577 133

598.7296 60 599 134

516.6675 95 517 135

528.6786 80 529 136

538.6738 85 539 137

533.6981 68 534 138

516.6675 91 517 139

489.598 85 490 140

475.5709 83 476 141

503.6251 85 504 142

489.598 91 490 143

461.5438 78 462 144

539.6586 88 540 145

539.6586 58 538 146

511.6044 80 512 147

505.6411 90 506

TABLE 3 MW Ex. No. Structure [g/mol] HPLC MZ + H 148

565.70 38 566 149

643.77 85 644 150

525.63 80 526 151

525.63 78 526 152

560.63 51 561 153

503.65 78 504 154

522.63 82 523 155

502.60 84 503 156

488.57 83 489 157

536.66 82 537 158

490.63 90 491 159

537.65 83 538 160

504.66 91 505 161

589.81 65 590 162

488.61 88 489 163

566.73 32 567 164

501.61 75 502 165

491.61 91 492 166

477.59 73 478 167

525.63 81 526 168

488.57 70 489 169

511.60 76 512 170

568.70 50 569 171

554.67 63 555 172

582.73 50 583 173

637.76 30 638 174

554.67 70 555 175

568.70 44 569

TABLE 4 MW Ex. No. Structure [g/mol] HPLC MZ + H 176

477.59 82 478 177

491.61 89 492 178

505.64 88 506 179

513.62 47 514 180

504.66 83 505 181

552.70 83 553 182

492.60 72 493 183

593.75 52 594 184

504.66 82 505 185

582.75 59 583 186

566.68 60 567 187

579.73 30 580 188

548.63 73 549 189

548.63 72 549 190

559.67 54 560 191

511.60 70 512 192

580.76 68 581 193

476.60 89 477 194

583.71 80 584 195

505.64 84 506 196

518.68 40 519 197

528.68 82 ? 529 198

566.68 63 567 199

553.69 87 554 200

491.61 84 492

TABLE 5 Ex. MZ + No. Structure MW HPLC H 201

516.67 87 517 202

502.64 84 503 203

516.67 87 517 204

538.67 91 539 205

533.7 85 534 206

518.68 77 519 207

566.73 92 567 208

552.7 87 553 209

506.63 52 507 210

560.72 62 561 211

568.7 88 569 212

582.73 89 583 213

580.71 83 581 214

518.64 89 519 215

463.56 90 464 216

548.71 78 549 217

490.63 87 491 218

532.71 93 533 219

564.71 91 565 220

556.73 92 557 221

516.67 92 517 222

504.66 83 505 223

558.75 90 559 224

532.71 86 533 225

572.78 68 573 226

582.73 87 583 227

548.71 85 549 228

594.78 97 595 229

590.75 90 591 230

530.69 95 531 231

542.71 88 543 232

552.7 91 553 233

534.68 65 535 234

520.66 83 521 235

530.69 89 531 236

542.71 70 543 237

580.71 81 581 238

504.66 81 505 239

551.67 86 552 240

518.68 85 519 241

502.64 85 503 242

580.76 79 581

TABLE 6 Ex. MZ + No. Structure MW HPLC H 243

477.5869 86 478 244

495.605 62 496 245

511.6044 50 512 246

564.495 40 565 247

555.658 61 556 248

497.5773 60 498 249

581.6963 77 582 250

557.6303 76 558 251

539.615 74 540 252

515.5677 64 516 253

472.5266 38 473 254

459.5715 88 460 255

551.5486 78 552 256

574.6824 59 575 257

497.5773 40 498 258

459.5715 90 460 259

473.5986 80 474 260

461.5439 83 462 261

503.6687 71 504 262

517.6086 71 518 263

511.6044 76 512 264

518.5989 74 519 265

552.6573 91 553 266

566.6844 71 567 267

567.6692 48 568 268

477.6084 90 478 269

569.6851 73 570 270

651.766 65 652 271

541.6309 71 542 272

607.6133 39 608 273

511.6044 92 512 274

589.7164 >95 590 275

477.5869 >95 478 276

463.5598 64 464 277

449.5327 >95 450 278

507.6134 >95 508 279

532.6232 >95 533 280

560.6775 89 561 281

636.8199 88 637 282

476.5585 50 477 283

489.5981 93 490 284

622.7928 68 623 285

608.7657 >95 609 286

583.6873 85 584 287

511.6044 >95 512 288

541.6309 >95 542 289

541.6309 >95 542 290

571.6574 73 572 291

569.6851 83 570 292

597.7393 89 598 293

581.6963 76 582 294

609.7504 83 610 295

609.7504 77 610 296

583.7122 82 584 297

611.7227 88 612 298

571.6574 89 572 299

567.6692 81 568 300

627.7221 82 628 301

661.7396 64 662 302

599.668 77 600 303

555.658 83 556 304

654.7916 60 655 305

626.7374 86 627 306

627.7221 82 628 307

583.7122 81 584 308

631.7568 29 632 309

569.6851 60 570 310

597.7393 62 598 311

581.6963 87 582 312

609.7504 71 610 313

633.7291 47 634 314

570.629 59 571 315

633.7291 35 634 316

583.7122 51 584 317

611.7227 51 612 318

571.6574 75 572 319

603.7026 64 604 320

567.6692 74 568 321

597.652 88 598 322

627.7221 80 628 323

647.7562 47 648 324

555.658 43 556 325

654.7916 54 655 326

624.7214 71 625 327

689.8375 42 690 328

583.7122 40 584 329

555.658 49 556 330

525.6315 83 526 331

525.6315 71 526 332

555.658 91 556 333

477.5869 76 478 334

478.5745 62 479 335

490.6292 42 491

Example 3362-[2-Ethoxy-5-(4-ethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazol[5,1-f][1,2,4]triazine-4-onehydrochloride trihydrate

If the free base from Example 19 is crystallized from a mixture of anorganic solvent and dilute aqueous hydrochloric acid, a hydrochloridetrihydrate is obtained.

m.p.: 218° C.

Water content: 9.4% (K. Fischer)

Chloride content: 6.1%

Example 3372-[2-Ethoxy-5-(4-ethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-onedihydrochloride

0.35 g (0.712 mmol) of2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-oneare suspended in 8 ml of ether and dichloromethane is added until ahomogeneous solution is formed. 24 ml of a 1M solution of HCl in etherare added and the mixture is stirred at room temperature for 20 minutesand filtered off with suction. This gives 372 mg (99%) of2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-onedihydrochloride.

200 MHz ¹H-NMR (DMSO-d₆): 0.96, t, 3H, 1.22, t, 3H, 1.36, t, 3H, 1.82,sex., 2H, 2.61, s, 3H, 2.88, m, 2H, 3.08, m, 6H, 3.50, m, 2H, 3.70, m,2H, 4.25, quart., 2H, 7.48, d, 1H; 7.95, m, 2H, 11.42, s, 1H, 12.45, s,1H.

1. A compound of the formula:

or a salt, a hydrate, or a hydrate of a salt thereof.
 2. The compoundaccording to claim 1 having the chemical name2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-onehydrochloride.
 3. The compound according to claim 1 having the chemicalname2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-onehydrochloride trihydrate.
 4. A pharmaceutical composition comprising acompound according to claim 1 and a pharmacologically acceptableformulating agent.
 5. A method of treating erectile dysfunctioncomprising administering to a mammal an effective amount of a compoundaccording to claim
 1. 6. The method of treating erectile dysfunctionaccording to claim 5 wherein the mammal is a human.